1521-0081/68/1/168–241$25.00 http://dx.doi.org/10.1124/pr.115.011411PHARMACOLOGICAL REVIEWS Pharmacol Rev 68:168–241, January 2016Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
ASSOCIATE EDITOR: MARKKU KOULU
Role of Cytochrome P450 2C8 in Drug Metabolism andInteractions
Janne T. Backman, Anne M. Filppula, Mikko Niemi, and Pertti J. Neuvonen
Department of Clinical Pharmacology, University of Helsinki (J.T.B., A.M.F., M.N., P.J.N.), and Helsinki University Hospital, Helsinki,Finland (J.T.B., M.N., P.J.N.)
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169II. Basic Characteristics of Cytochrome P450 2C8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
A. Genomic Organization and Transcriptional Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170B. Protein Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171C. Expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
III. Substrates of Cytochrome P450 2C8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173A. Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
1. Anticancer Agents.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1732. Antidiabetic Agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1833. Antimalarial Agents.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1834. Lipid-lowering Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1845. Other Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1846. Glucuronide Metabolites.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
B. Endogenous and Natural Compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187IV. Pharmacogenetics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
A. Population Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187B. Functional Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191C. Effects on Drug Metabolism in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
V. In Vitro Inhibition and Induction of Cytochrome P450 2C8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193A. Reversible Inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
1. Drugs That Act as Inhibitors of Cytochrome P450 2C8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1932. Natural Compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
B. Metabolism-dependent Inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210C. Induction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
VI. Clinical Drug Interactions Mediated via Cytochrome P450 2C8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212A. General Aspects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212B. Gemfibrozil as Prototypical Inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
1. In Vitro Versus In Vivo.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2142. Gemfibrozil Dose Versus CYP2C8 Inhibition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2163. Onset and Duration of CYP2C8 Inhibition by Gemfibrozil. . . . . . . . . . . . . . . . . . . . . . . . . . . . 2164. Quantification of CYP2C8-Mediated Drug Interactions in Humans. . . . . . . . . . . . . . . . . . . 216
C. Inhibition-Mediated Drug Interactions and Their Clinical Significance . . . . . . . . . . . . . . . . . . 2171. Repaglinide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2172. Other Oral Antidiabetic Drugs.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2183. Amodiaquine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2194. Statins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2195. Anticancer Drugs.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
This work was supported by grants from the Academy of Finland [Grant decision 278123, 2014], the Helsinki University Central HospitalResearch Fund, and the Sigrid Juselius Foundation (Helsinki, Finland).
Address correspondence to: Prof. Janne T. Backman, Department of Clinical Pharmacology, University of Helsinki and HelsinkiUniversity Hospital, P.O. Box 705, FI-00029 HUS, Finland. E-mail: [email protected]
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6. Antiviral Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2217. Antiasthmatic Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2218. Other Substrate or Inhibitor Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
D. Induction-Mediated Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2221. Rifampin (Rifampicin). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
VII. Points to Consider When Investigating Cytochrome P450 2C8-Mediated DrugMetabolism and Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222A. In Vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
1. General Aspects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2222. Assessment of CYP2C8 Activity In Vitro. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2233. In Vitro Methods to Estimate the Contribution of CYP2C8 in the Metabolism
of a Drug. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224B. In Vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
1. General Aspects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2242. In Vivo Cytochrome P450 2C8 Probe Substrates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2263. In Vivo Cytochrome P450 2C8 Probe Inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
VIII. Conclusions and Future Prospects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
Abstract——During the last 10-15 years, cytochromeP450 (CYP) 2C8 has emerged as an important drug-metabolizing enzyme. CYP2C8 is highly expressed inhuman liver and is known to metabolize more than 100drugs. CYP2C8 substrate drugs include amodiaquine,cerivastatin, dasabuvir, enzalutamide, imatinib,loperamide, montelukast, paclitaxel, pioglitazone,repaglinide, and rosiglitazone, and the number isincreasing. Similarly, many drugs have been identifiedasCYP2C8 inhibitors or inducers. In vivo, already a smalldose of gemfibrozil, i.e., 10% of its therapeutic dose, is astrong, irreversible inhibitor of CYP2C8. Interestingly,recent findings indicate that the acyl-b-glucuronidesof gemfibrozil and clopidogrel cause metabolism-dependent inactivation of CYP2C8, leading to a strongpotential for drug interactions. Also several other
glucuronide metabolites interact with CYP2C8 assubstrates or inhibitors, suggesting that an interplaybetween CYP2C8 and glucuronides is common. Lack offully selective and safe probe substrates, inhibitors,and inducers challenges execution and interpretationof drug-drug interaction studies in humans. Apart fromdrug-drug interactions, some CYP2C8 genetic variantsare associated with altered CYP2C8 activity and exhibitsignificant interethnic frequency differences. Herein,wereviewthecurrentknowledgeonsubstrates, inhibitors,inducers, and pharmacogenetics of CYP2C8, as well asits role in clinically relevant drug interactions. Inaddition, implications for selection of CYP2C8 markerand perpetrator drugs to investigate CYP2C8-mediateddrug metabolism and interactions in preclinical andclinical studies are discussed.
I. Introduction
Cytochrome P450 (CYP) 2C8 accounts for approxi-mately 6–7% of the total hepatic CYP content (RowlandYeo et al., 2004; Inoue et al., 2006; Rostami-Hodjegan andTucker, 2007; Achour et al., 2014). The importance ofCYP2C8 causing variation in drug response via drug-druginteractions and pharmacogenetic polymorphisms hasbeen recognized only for the last 10–15 years. In thebeginning of the millennium, the pharmacokinetic drug-drug interaction between the fibric acid derivative gemfi-brozil and the 3-hydroxy-3-methylglutaryl-coenzyme A
(HMG-CoA) reductase inhibitor cerivastatin, a CYP2C8substrate, resulting in rhabdomyolysis cases and fatalitiesbrought attention to the importance of CYP2C8 in drugmetabolism (Backman et al., 2002; Staffa et al., 2002;Wang et al., 2002; Chang et al., 2004; Huang et al., 2008).The event was the onset of a broadening scientific in-terest in CYP2C8, promptly convincing drug regulatoryauthorities to acknowledge CYP2C8 as one of the majordrug-metabolizing CYP enzymes.
Drugs that were introduced into clinical use beforethe role of CYP2C8 was recognized may have deficient
ABBREVIATIONS: AUC, area under the plasma concentration-time curve; C/EBPa, CCAAT/enhancer-binding protein a; CAR,constitutive androstane receptor; CITCO, [6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime;CLint, intrinsic clearance; Cmax, peak concentration; CYP, cytochrome P450; EMA, European Medicines Agency; FDA, Food and DrugAdministration; GR, glucocorticoid receptor; HLM, human liver microsomes; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; HNF,hepatic nuclear factor; I, inhibitor concentration; Ki, reversible inhibition constant; KI, inhibitor concentration supporting half of themaximal rate of enzyme inactivation; kinact, maximal rate of inactivation; Km, Michaelis-Menten constant; MRL-C, 2-[[5,7-dipropyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy]-2-methylpropanoic acid; mRNA, messenger ribonucleic acid; OAT, organic anion transporter;OATP, organic anion-transporting polypeptide; PPAR, peroxisome proliferator activated receptor; PXR, pregnane X receptor; ROR, retinoicacid-related orphan receptors; SIFT, sorting intolerant from tolerant; SNV, single nucleotide variation; t1/2, elimination half-life; tmax, timeto peak concentration; UGT, uridine-59-diphosphoglucuronosyltransferase; VDR, vitamin D receptor.
Role of CYP2C8 in Drug Metabolism and Interactions 169
or incorrect product information regarding their in-teraction potential (Neuvonen, 2012). One example isthe leukotriene receptor antagonist montelukast.Early preclinical studies concluded that CYP2C9 andCYP3A4 are themost important enzymes involved in itsmetabolism, whereas the role of CYP2C8 was notevaluated (Chiba et al., 1997). In interaction studiesperformedmore than a decade later, the strong CYP2C8inhibitor gemfibrozil increased the plasma exposureto montelukast almost fivefold, whereas the strongCYP3A4 inhibitor itraconazole had no significant effecton its pharmacokinetics (Karonen et al., 2010, 2012).The clinical findings were corroborated by in vitro data,showing that CYP2C8 is the main enzyme involved inthe oxidative metabolism of montelukast (Filppulaet al., 2011; VandenBrink et al., 2011).The large, trifurcated active site cavity of CYP2C8 is
able to accommodate substrates of different shapes andsizes (Schoch et al., 2008). Today, CYP2C8 is known toparticipate in the metabolism of more than 100 drugs,including amodiaquine, cerivastatin, dasabuvir, enzalu-tamide, imatinib, loperamide, montelukast, paclitaxel,pioglitazone, repaglinide, and rosiglitazone. The num-ber of drugs that are identified as CYP2C8 substratesor inhibitors, as well as CYP2C8-mediated drug-druginteractions is continuously increasing. The strongCYP2C8 inhibition by gemfibrozil observed in vivo isdue to its acyl-b-glucuronide metabolite, which is apotent mechanism-based inhibitor of CYP2C8 (Ogilvieet al., 2006). Also other glucuronidemetabolites of drugswere recently found to interact with CYP2C8 either assubstrates or inhibitors. For instance, the acyl-b-D-glucuronide metabolite of clopidogrel is a metabolism-dependent inhibitor of CYP2C8, causing more than afivefold increase in the plasma exposure to repaglinidein healthy subjects (Tornio et al., 2014). In anotherrecent in vitro study, CYP2C8 metabolized the glucu-ronide metabolite of desloratadine to its pharmacolog-ically active 3-hydroxydesloratadine metabolite (Kazmiet al., 2015). These and other data suggest that aninterplay between CYP2C8 and glucuronide metabo-lites may be more a rule than an exception.There are several common nonsynonymous varia-
tions in the CYP2C8 gene (Daily and Aquilante, 2009;Aquilante et al., 2013b). For example, the CYP2C8*3allele has been associated with decreased metabolismof several substrates, e.g., paclitaxel, in vitro (Dai et al.,2001). In contrast, clinical data indicate that theCYP2C8*3allele is often associated with increased metabolism ofCYP2C8 substrates, such as repaglinide (Niemi et al.,2003c). Thus, although complete lack of function variantsin CYP2C8 are rare, the possible substrate dependencyof the functional consequences of the common CYP2C8variants and their potential clinical significance haveraiseda lot of interest towardCYP2C8pharmacogenetics.The structural properties, regulation of expression,
pharmacogenetics, substrates, inhibitors, and physiologic
roles of CYP2C8 have been thoroughly examined anddiscussed in several previous reviews (Kirchheiner et al.,2005; Totah and Rettie, 2005; Garcia-Martin et al., 2006;Gil and Gil Berglund, 2007; Agundez et al., 2009; ChenandGoldstein, 2009;Daily andAquilante, 2009; Lai et al.,2009; Aquilante et al., 2013b; Fleming, 2014; Xiaopinget al., 2013). Thus, the reader will be directed to theseearlier works for some previously known aspects relatedto CYP2C8. Herein, our intention is to review and updatethe current knowledge on substrates, inhibitors, in-ducers, and pharmacogenetics of CYP2C8, as well as itsrole in clinically relevant drug interactions. In addition,implications for selection of CYP2C8 marker and perpe-trator drugs to investigate CYP2C8-mediated drug me-tabolism and interactions in preclinical and clinicalstudies are discussed.
II. Basic Characteristics of Cytochrome P450 2C8
A. Genomic Organization and Transcriptional Regulation
The CYP2C8 enzyme is encoded by theCYP2C8 gene,which is located on the chromosome 10q24 in the 2Cgene cluster centromere-2C18-2C19-2C9-2C8-telomerein close proximity of the CYP2C9 gene (Fig. 1; Grayet al., 1995; Klose et al., 1999). CYP2C8 is the smallestof the human CYP2C genes; it spans a 31-kb region andcontains 9 exons (Klose et al., 1999; Lai et al., 2009). Itshares 74% sequence homology with CYP2C9 (Dailyand Aquilante, 2009).
The transcriptional regulation of CYP2C8 is mediatedvia several transcriptional factors and distinct nuclearreceptors that can activate the respective responsiveelements within the 59-flanking promoter region of thegene (Ferguson et al., 2005; Johnson and Stout, 2005;Kojima et al., 2007; Chen and Goldstein, 2009). Suchfactors/receptors include the constitutive androstane re-ceptor (CAR), pregnane X receptor (PXR), vitamin Dreceptor (VDR), glucocorticoid receptor (GR), hepaticnuclear factor-4a (HNF4a), HNF3g, CCAAT/enhancer-binding protein a (C/EBPa), and retinoic acid-relatedorphan receptors (RORs) (Fig. 1; Ferguson et al., 2005;Chen and Goldstein, 2009; Rana et al., 2010; Aquilanteet al., 2013b). Although HNF4a, HNF3g, C/EBPa, andRORs seem to mainly regulate the constitutive expressionof CYP2C genes in liver, the other receptors are moreimportant to thexenobiotic-mediated inductionofCYP2C8expression, as described in more detail in section V.C.
After activation by endo- or xenobiotics, CAR, PXR,and VDR form heterodimers with the retinoid Xreceptor, whereas GR forms homodimers (Chen andGoldstein, 2009). These dimers are thereafter recog-nized by specific response elements within the CYP2C8promoter. By using in vitro gel shift assays, responsiveelements/motifs within the CYP2C8 promoter regionshave been identified for CAR, PXR, and GR (Gerbal-Chaloin et al., 2002; Ferguson et al., 2005; Chen andGoldstein, 2009).
170 Backman et al.
After activation, the orphan nuclear receptor HNF4abinds as a homodimer to a DR1 type element and alsoto the Hep-G2 specific P450 factor-1 motif (Venepallyet al., 1992), whereas HNF3g binds to DNA as amonomer (Bort et al., 2004). At least two Hep-G2specific P450 factor-1 motifs and several putativeHNF3g binding sites have been identified within thepromoter of CYP2C8 (Bort et al., 2004; Ferguson et al.,2005; Chen and Goldstein, 2009). RORs are constitu-tively active orphan nuclear receptors, which havenatural ligands, such as all-trans-retinoic acid thatcan influence their activity. Also RORs seem to beinvolved in the constitutive regulation of CYP2C8,and at least two ROR responsive elements have beenidentified in the gene promoter (Chen et al., 2009).Transcriptional regulation of CYP2C8 has been re-viewed thoroughly by Chen and Goldstein (2009).
B. Protein Structure
The crystal structure of CYP2C8was resolved in 2004(Schoch et al., 2004). A single CYP2C8 crystal dif-fracted to 2.7 Å and had the molecular weight approx-imated to 54 kDa. Interestingly, CYP2C8 crystallized asa symmetric dimer formed by interactions between thehelix F to G regions of the two monomers. Two palmiticacid molecules were bound in the dimer interface,stabilizing the dimer. Thus, the two fatty acids mayform a peripheral binding site, which may affect thestructural dynamics of the active site and influencereactions catalyzed by CYP2C8. The active site volumeof CYP2C8 was estimated to 1,438 Å3 (Schoch et al.,
2004), which is similar to that of CYP3A4 (1,386 Å3)but larger than those of CYP1A2 (375 Å3), CYP2A6(260 Å3), CYP2C9 (;470 Å3), CYP2D6 (;540 Å3), andCYP2E1 (190 Å3) (Williams et al., 2003; Yano et al.,2004; Rowland et al., 2006; Sansen et al., 2007;Porubsky et al., 2008). Although CYP3A4 has a uni-formly distributed active site cavity, that of CYP2C8 istrifurcated, resembling a T or Y shape (Schoch et al.,2008). The bottom branch of the cavity provides accessto the heme, and the two other terminate in solvent andsubstrate access channels that exit the active site cavityon either side of the helix B-C loop.
In the X-ray crystallography study, the N-terminalanchor domains of both CYP2C8 molecules were lo-cated on the same side of the dimer, indicating anorientation compatible with membrane binding (Schochet al., 2004). The proximal surfaces of each protein wereroughly parallel, suggesting that they are accessible forinteraction with the membrane-bound CYP oxidoreduc-tase. Another study demonstrated that the dimericstructure observed in the crystal structure of CYP2C8may also be present inmembrane-bound native CYP2C8(Hu et al., 2010). The signal anchor/linker regions ofnative CYP2C8 formed a second dimerization interface,and it was suggested that this interaction is requiredfor the formation of the dimer of the native protein.Although direct evidence for a functional significanceof the dimerization is lacking, such interactionshave been shown to affect activities of other CYPs andmembrane proteins in the endoplasmic reticulum (Huet al., 2010).
Fig. 1. The CYP2C8 gene is located to the CYP2C gene cluster on chromosome 10. C/EBPa, CCAAT/enhancer-binding protein a; CAR, constitutiveandrostane receptor; GR, glucocorticoid receptor; HNF, hepatic nuclear factor; PXR, pregnane X receptor; ROR, retinoic acid-related orphan receptor;VDR, vitamin D receptor.
Role of CYP2C8 in Drug Metabolism and Interactions 171
According to the X-ray crystallographic data, theactive site cavity of CYP2C8 is capable of bindingstructurally diverse substrates without major changesin its tertiary structure (Schoch et al., 2008). Ligands ofCYP2C8 may bind to the active site differently, fillingthe cavity either partially or completely or occupying itwith two molecules simultaneously. For instance, mon-telukast, a large anionic molecule with a tripartitestructure, complemented the size and shape of thewhole active-site cavity. The linearly shaped troglita-zone molecule occupied the upper portion of the cavity,leaving a significant part of the cavity empty, whereastwomolecules of 9-cis-retinoic acid were simultaneouslypresent in the substrate-binding cavity of CYP2C8(Schoch et al., 2008). The interactions between CYP2C8and its substrates were predominantly hydrophobic.In addition, the distal region of the CYP2C8 active
site cavity contains a number of polar amino acid sidechains and exposed peptide backbone hydrogen bonddonors and acceptors (Schoch et al., 2008). Accordingly,for example, the residues Ser-100, Ser-103, Asn-204,Asn-217, and Arg-241 form hydrogen bonds involved inthe binding of the CYP2C8 substrates retinoic acid,troglitazone and montelukast. Of note, a pronouncedside chain movement was observed in crystallizedcomplexes with troglitazone and retinoic acid, whereArg-241was reoriented to the inside of the cavity, whereit could provide a strong, charge-stabilized hydrogenbond with the substrate. Interestingly, according tocomputational docking simulations, the glucuronidemoieties of gemfibrozil 1-O-b glucuronide and clopidog-rel acyl 1-b-D-glucuronide are oriented toward the samehydrophilic area in the active site close to helix B9,
where Ser-100 and Ser-103 reside (Fig. 2; Baer et al.,2009; Tornio et al., 2014).
Although the large active site of CYP2C8 anddiversity of its substrates (section III) may complicatethe use of a general pharmacophore model, analysis ofeight CYP2C8 substrates showed that the majority ofthese compounds contained a terminal anionic or polargroup ;13 Å from the oxidation site, and one or twosecondary polar moieties ;4.5 Å and ;8.5 Å from theoxidation site (Melet et al., 2004). The pharmacophoremodel and previously reported homology models forCYP2C8 have been comprehensively reviewed by Laiand colleagues (2009).
C. Expression
According tometa-analyses, themean hepatic CYP2C8concentration approximates to 22–24 pmol/mg and14 pmol/mg in adult Caucasian and Japanese livers,respectively (Rowland Yeo et al., 2004; Inoue et al.,2006; Rostami-Hodjegan and Tucker, 2007; Achouret al., 2014). The interindividual variability of CYP2C8protein expression in liver is high, with coefficients ofvariation of 68–95%. The protein expression levelof CYP2C8 seems to be highly correlated with bothits enzyme activity and messenger ribonucleic acid(mRNA) expression level (Ohtsuki et al., 2012).
Hepatic CYP2C8 mRNA and protein are expressedearly in the prenatal development and reaches adultlevels already in early childhood (Treluyer et al., 1997;Blanco et al., 2000; Naraharisetti et al., 2010; Cizkovaet al., 2014; Johansson et al., 2014). CYP2C8 seems to bethe predominant CYP2C isoform in fetal livers (Hak-kola et al., 1994; Nishimura et al., 2003; Johansson
Fig. 2. Stereoimage of three independent docking simulations of the interaction between clopidogrel acyl 1-b-D-glucuronide and the active site ofCYP2C8. Clopidogrel acyl-b-D-glucuronide is rendered with gray sticks depicting carbon atoms. The distance between clopidogrel acyl-b-D-glucuronidethiophene ring carbon and heme iron is indicated by a green line. Other atoms of the clopidogrel acyl-b-D-glucuronide molecule are colored red foroxygen, blue for nitrogen, yellow for sulfur, and green for chlorine.
172 Backman et al.
et al., 2014). In a recent study, CYP2C8 mRNA wasexpressed in all fetal tissues studied (adrenal, kidney,liver, and lung tissue), whereas CYP2C9 mRNA wasrestricted to the liver (Johansson et al., 2014). Anotherstudy detected CYP2C8, CYP2C9, and CYP2C19 pro-tein in fetal liver, intestine, and kidney (Cizkova et al.,2014). One explanation for the role of CYP2C8 in thefetus during early pregnancymay be a need for CYP2C8to metabolize endogenous compounds such as retinoicacids and hence protect the fetus from retinoic acid-induced embryotoxicity (Johansson et al., 2014).In adults, CYP2C8 mRNA has been detected in
numerous extrahepatic tissues, including the adrenalgland, arteries, brain, duodenum, heart, kidney, lung,mammary gland, ovary, prostate, retina; testis, anduterus, but not in placenta (Zeldin et al., 1995; Maceet al., 1998; McFayden et al., 1998; Klose et al., 1999;Thum and Borlak, 2000; Nishimura et al., 2003;Delozier et al., 2007; Dutheil et al., 2009; Capozzi et al.,2014). CYP2C8 protein has been detected in heart,hepatocytes, kidney, salivary ducts, small and largeintestine, adrenal cortical cells, and tonsils (Läppleet al., 2003; Enayetallah et al., 2004; Delozier et al.,2007; Cizkova et al., 2014). The expression of CYP2C8and other CYP enzymes has recently been reviewed byShahabi et al. (2014).Analysis of liver samples has recently shown that a
nearly full-length form of CYP2C8 (wild type) and anN-terminal truncated splice variant 3 are expressed inmitochondria (Bajpai et al., 2014). Although the wild-type protein was detected only at low levels in mito-chondria (,25%), variant 3 was primarily targeted tomitochondria and minimally to the endoplasmic re-ticulum. Interestingly, although molecular modelingshowed that both the heme binding pocket and thesubstrate binding cavity were nearly intact in variant3, it was unable to catalyze paclitaxel 6-hydroxylationin human hepatocellular liver carcinoma cells. How-ever, it did metabolize smaller substrates such asarachidonic acid and dibenzylfluorescein. Further-more, the variant generated higher levels of reactiveoxygen species and showed a higher level of mitochon-drial respiratory dysfunction than wild type CYP2C8,suggesting that the mitochondrially targeted variant 3may contribute to oxidative stress in tissues (Bajpaiet al., 2014).In living organisms, CYP enzymes undergo natural
degradation that can be described as a first-order process(Yang et al., 2008). Therefore, the expression level ofthe enzyme is determined by the rate of enzymesynthesis and the degradation half-life of the enzyme.The extent and dose and time dependency of enzymeinduction and inactivation are thus also dependent onthe degradation half-life. Based on clinical studieswith the CYP2C8 inactivator gemfibrozil, the degra-dation (turnover) half-life of CYP2C8 is approximately22 hours (Backman et al., 2009).
III. Substrates of Cytochrome P450 2C8
CYP2C8 participates in the metabolism of numerousdrugs and some endogenous and natural compounds. Itcatalyzes a variety of oxidative reactions, in particularhydroxylations, N-demethylations, and N-deethyla-tions (Tables 1–4). Because of its large, sinuous activesite, CYP2C8 can accommodate substrates of differentsizes and structures. The molecular weight of drugssignificantly metabolized by CYP2C8 (.20%; Table 1)ranges from 206 to 854 g/mol, with amedian of 451 g/mol(Fig. 3).
Most, if not all, of the drugs significantly metabolizedby CYP2C8 are also substrates of other CYP enzymes(Table 1), with about 75% beingmetabolized byCYP3A4and ;30% by CYP2C9. However, the metabolic prod-ucts generated by CYP2C8 and CYP3A4 are oftendifferent. For instance, CYP2C8 metabolizes paclitaxelto 6a-hydroxypaclitaxel, whereas CYP3A4 exclusivelygenerates 39-hydroxypaclitaxel (Rahman et al., 1994),suggesting that compounds that are substrates of bothCYP2C8 and CYP3A4 bind differently to their activesites.
A. Drugs
CYP2C8 is involved in the metabolism of more than100 clinically used drugs (Table 1). Typical substratedrugs of CYP2C8 include anticancer, antidiabetic,antimalarial, and lipid-lowering agents (Fig. 4). In-terestingly, some glucuronide metabolites of drugs in-teract with CYP2C8.
1. Anticancer Agents. The antimicrotubule agentpaclitaxel with a molecular weight of 853.9 g/mol isone of the largest substrates of CYP2C8. In vitro,paclitaxel is primarily metabolized by CYP2C8 to itsmain 6a-hydroxy metabolite and by CYP3A4 to 39-phenyl-hydroxypaclitaxel, and the further metabolismof these metabolites results in the formation of 6a, 39-p-dihydroxypaclitaxel (Cresteil et al., 1994, 2002; Harriset al., 1994; Kumar et al., 1994; Rahman et al., 1994).Paclitaxel 6a-hydroxylation is recommended by drugauthorities as a marker reaction for CYP2C8 acti-vity in vitro (EMA, 2012b; http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm), and it hasbeenwidely used in preclinical studies. In amass balancestudy in patients,metabolites accounted for about 40% ofthe total systemic drug exposure, and the excreted 6a-hydroxypaclitaxel corresponded to almost one-third ofthe administered dose (Walle et al., 1995), suggestingthat ;30–40% of a paclitaxel dose is converted byCYP2C8 to 6a-hydroxy paclitaxel.
Cabazitaxel, a taxane approved in 2010, is alsometabolized by CYP2C8 to a small extent in vitro(FDA, 2010a), whereas there is conflicting data re-garding the role of CYP2C8 in the metabolism ofdocetaxel. One in vitro study demonstrated that
Role of CYP2C8 in Drug Metabolism and Interactions 173
TABLE 1Drugs that are metabolized by CYP2C8, grouped by the importance of CYP2C8 in their elimination (Major, intermediate, minor)
Substrate Therapeutic Use and/orDrug Class
Metabolic Pathway(s)Catalyzed by CYP2C8
Other CYP EnzymesInvolved in Overall
MetabolismaReferences
Major (.70%)Amodiaquine Antimalarial N-deethylation (CYP1A1, CYP1B1) Li et al., 2002Cerivastatin (acid,
parent)Antihyperlipidemic, HMG-
CoA reductase inhibitor6-hydroxylation (M-23),
demethylation (M-1)CYP3A4 Backman et al., 2002
Daprodustat(GSK1278863)
Antianemic, prolylhydroxylase inhibitor
CYP3A4 Johnson et al., 2014
Dasabuvir (ABT-333) Antiviral, NSB5 inhibitor M1 formation CYP3A4, CYP2D6 FDA, 2014gEnzalutamide Anticancer, antiandrogen Hydroxylation (M6),
N-demethylation (M2)CYP3A4/5 FDA, 2012k; Gibbons et al.,
2015Montelukast Antiasthmatic, LTRA 36-hydroxylation (M6),
25-hydroxylation(M3), M4 formation
CYP3A4, CYP2C9 Karonen et al., 2010;Filppula et al., 2011
Pioglitazone Antidiabetic, PPAR-gagonist
Hydroxylation CYP3A4/5, CYP1A1 Jaakkola et al., 2006c; FDA,2013a
Repaglinide Antidiabetic, meglitinideanalog
M2 and M4 formation CYP3A4 Bidstrup et al., 2003;Kajosaari et al., 2005a
Intermediate (20–70%)9cUAB30 Anticancer, retinoid M1-M5 formation CYP2C9, CYP2C19,
(CYP1A2, CYP2B6)Gorman et al., 2007
Acotiamide (Z-338) Antidyspeptic,acetylcholinesteraseinhibitor
Deisopropylation (M-4) CYP1A1, CYP3A4 Furuta et al., 2004; PMDA,2014
Alitretinoin (9-cis-retinoic acid)
Antipsoriatic, retinoid 4-hydroxylation CYP2C9, CYP3A4,CYP26A1
Marill et al., 2002
Amiodarone Antiarrhythmic N-deethylation CYP3A4, (CYP1A2,CYP2C19, CYP2D6)
Ohyama et al., 2000
Chloroquine Antimalarial N-deethylation CYP3A4/5, (CYP2D6) Kim et al., 2003; Projeanet al., 2003a
(2)(+)-Cisapride Gastroprokinetic, 5-HT4receptor agonist
N-dealkylation, 4-hydroxylation, 2-hydroyxlation
CYP3A4, CYP2B6 Desta et al., 2000, 2001
Compound A ERA Hydroxylation Ma et al., 2004Dabrafenib Anticancer, PKI Hydroxylation CYP3A4/5, (CYP2C9,
CYP2C19)Lawrence et al., 2014;
Suttle et al., 2015Fenretinide Anticancer, retinoid 49-hydroxylation,
49-oxidationCYP3A4/5 Illingworth et al., 2011
R/S-Fluoxetine Antidepressant, SSRI N-demethylation CYP2C9, CYP2D6 Wang et al., 2014bR-Ibuprofen Anti-inflammatory, NSAID 2-hydroxylation,
3-hydroxylationCYP2C9 Hamman et al., 1997;
Tornio et al., 2007;Chang et al., 2008
Imatinib Anticancer, PKI N-demethylation CYP3A4/5 Nebot et al., 2010; Filppulaet al., 2013a,b
Irosustat Anticancer, STS inhibitor M9 and M13 formation CYP2C9, CYP3A4/5,(CYP2E1)
Ventura et al., 2011
Isotretinoin (13-cis-retinoic acid)
Antiacne, retinoid 4-hydroxylation CYP3A4 Marill et al., 2002
Loperamide Antidiarrheal, opioid N-demethylation CYP3A4, CYP2B6, CYP2D6 Kim et al., 2004; Niemiet al., 2006
Olanzapine Antipsychotic N-demethylation CYP1A2, CYP2D6, CYP3A4 Korprasertthaworn et al.,2015
Olodaterol Antiasthmatic, LABA O-demethylation CYP2C9, (CYP3A4) FDA, 2014fPaclitaxel (taxol) Anticancer, taxane 6a-hydroxylation CYP3A4 Cresteil et al., 1994;
Rahman et al., 1994;Walle et al., 1995
Paritaprevir (ABT-450) Antiviral, NS3-4A inhibitor CYP3A4 FDA, 2014gPropanoic acid
dronedaroneDrug metabolite Hydroxylation (M10 and
M11)CYP1A1 Klieber et al., 2014
R483 Antidiabetic, PPAR-gagonist
M1 and M4 formation CYP2C19, CYP3A4,(CYP2C9)
Bogman et al., 2010
Rosiglitazone Antidiabetic, PPAR-gagonist
p-hydroxylation,N-demethylation
CYP2C9 Baldwin et al., 1999
Simvastatin acid Antihyperlipidemic, HMG-CoA reductase inhibitor
Oxidation (M1-M3) CYP3A4/5 Prueksaritanont et al., 2003
Tazarotenic acid Antipsoriatic, drugmetabolite (active)
Sulfoxidation Attar et al., 2003
Tozasertib (MK 0457,VX6, VX 680)
Anticancer, PKI N-demethylation CYP3A4 Ballard et al., 2007
Treprostinil Antihypertensive CYP2C9 FDA, 2009bTroglitazone Antidiabetic, PPAR-g
agonistQuinone metabolite
formationCYP3A4 Yamazaki et al., 1999b
(continued )
174 Backman et al.
TABLE 1—Continued
Substrate Therapeutic Use and/orDrug Class
Metabolic Pathway(s)Catalyzed by CYP2C8
Other CYP EnzymesInvolved in Overall
MetabolismaReferences
R/S-Verapamil Antihypertensive, CCB N-dealkylation, N-demethylation, O-demethylation
CYP3A4/5, (CYP2E1) Busse et al., 1995; Tracyet al., 1999
Vidupiprant (AMG 853) Antiasthmatic, PGD2receptor antagonist
t-butyl hydroxylation(M2), cyclopropylhydroxylation (M3)
CYP2J2, CYP3A Foti et al., 2012
Zopiclone Sedative, GABA receptoragonist
N-demethylation, N-oxidation
CYP3A4, CYP2C9 Becquemont et al., 1999;Tornio et al., 2006
Unknown or Minor(;,20%)
5-MeO-DIPT (Foxy) Hallucinogenic N-deisopropylation CYP2D6, CYP1A2,CYP3A4, CYP2C19
Narimatsu et al., 2006
7-Epi-10-deacetyl-paclitaxel
Paclitaxel derivative Hydroxylation CYP3A4 Zhang et al., 2009a
7-Epi-cephalomannine Paclitaxel derivative M-2 formation CYP3A4 Zhang et al., 2009a7-Epi-paclitaxel Paclitaxel epimer M-2 formation CYP3A4 Zhang et al., 2009b10-Aceyldocetaxel Docetaxel derivative 6-hydroxylation CYP3A4 Cresteil et al., 200210-Deacetylpaclitaxel Paclitaxel derivative 6-hydroxylation CYP3A4 Cresteil et al., 200217a-Ethinylestradiol Contraceptive, hormone
derivative2-hydroxylation Wang et al., 2004
17b-Estradiol (estradiol) Hormonal replacementtherapy
2-hydroxylation, 4-hydroxylation
CYP1A1, CYP1B1 Spink et al., 1992
Aminophenazone(aminopyrine)
Analgesic N-demethylation CYP2C19, CYP2B6,CYP2D6
Niwa et al., 1999, 2000
Amitriptyline Antidepressant, TCA N-demethylation CYP3A4/5, CYP2C19 Venkatakrishnan et al.,2001
Anastrozole Anticancer, aromataseInhibitor
Hydroxylation CYP3A4, CYP3A5 Kamdem et al., 2010
Apixaban Antithrombotic, factor Xainhibitor
O-demethylation CYP3A4, CYP1A2,CYP2C9, CYP2C19,CYP2J2
FDA, 2012d
Apremilast Antipsoriatic, PDE4inhibitor
M5 formation CYP3A4, CYP2A6,(CYP1A2, CYP2C9,CYP2E1)
FDA, 2014e
Artelinic acid Antimalarial 3-hydroxylation CYP3A4/5 Grace et al., 1999Atorvastatin (acid,
parent)Antihyperlipidemic, HMG-
CoA reductase inhibitorp-hydroxylation CYP3A4/5 Jacobsen et al., 2000b
Azilsartan Antihypertensive, ARB Decarboxylation (M-I),O-dealkylation (M-II)
CYP2C9, CYP2B6 FDA, 2011c
Bedaquiline Antibiotic, ATP synthaseinhibitor
N-demethylation CYP3A4, CYP2C19 Liu et al., 2014
Brinzolamide Antiglaucoma, carbonicanhydrase inhibitor
CYP3A4, CYP2A6,CYP2B6, CYP2C9
EMA, 2014
Brivaracetam Antiepileptic Hydroxylation CYP2C9, CYP3A4 Whomsley et al., 2007;Nicolas et al., 2012
Buprenorphine Analgesic, opioid N-dealkylation, M1formation
CYP3A4 Moody et al., 2002; Picardet al., 2005; Chang et al.,2006
Buspirone Anxiolytic CYP3A4 Karlsson et al., 2013BYZX Antidementia,
acetylcholinesteraseinhibitor
N-deethylation (M3) CYP3A4 Yu et al., 2013a
BYZX M2 Drug metabolite N-deethylation (M1) CYP3A4 Yu et al., 2013aCabazitaxel Anticancer, taxane RPR 112698 formation CYP3A4/5 FDA, 2010aCaffeine Psychostimulant N-demethylation,
C-8-hydroxylationCYP3A4, CYP1A2, CYP2C9 Kot and Daniel, 2008
Capravirine Antiviral, NNRTI Sulfoxidation (C23),N-oxidation (C26),hydroxylation (C19)
CYP3A4, CYP2C9,CYP2C19
Bu et al., 2006
Carbamazepine Antiepileptic 10,11-epoxidation,3-hydroxylation
CYP3A4 Kerr et al., 1994; Pelkonenet al., 2001
Cephalomannine Paclitaxel derivative 4a-hydroxylation Zhang et al., 2009aCerlapirdine Antidementia, 5-HT6
receptor antagonistDemethylation CYP3A4 Tse et al., 2014
Cilostazol Antithrombotic, PDE3inhibitor
OPC-13217 formation CYP3A4/5, CYP1B1,CYP2C19
Hiratsuka et al., 2007
Cinitapride Gastroprokinetic, 5-HT4receptor agonist
CYP3A4 Robert et al., 2007
E-Clomiphene Ovulation inducer, SERM Deethylation,hydroxylation
CYP3A4/5, CYP2D6 Mürdter et al., 2012
Clozapine Antipsychotic N-demethylation, oxidation CYP1A2,(CYP3A4)
Linnet and Olesen, 1997
(continued )
Role of CYP2C8 in Drug Metabolism and Interactions 175
TABLE 1—Continued
Substrate Therapeutic Use and/orDrug Class
Metabolic Pathway(s)Catalyzed by CYP2C8
Other CYP EnzymesInvolved in Overall
MetabolismaReferences
CPI-613 Anticancer,antimitochondrialmetabolism agent
CYP3A4, (CYP2C9,CYP2C19)
Lee et al., 2011
Cyamemazine Antipsychotic N-demethylation CYP1A2, CYP3A4, CYP2C9 Arbus et al., 2007Cyclophosphamide Anticancer, alkylating
agent4-hydroxylation CYP2C9, CYP2A6,
CYP2B6, CYP3A4Chang et al., 1993; Huang
et al., 2000Cyclosporine Immunosuppressant,
calcineurin inhibitorCYP3A4 Karlsson et al., 2013
Dapsone Antimicrobial N-hydroxylation CYP2C9 Winter et al., 2000Diazepam Anxiolytic, benzodiazepine N-demethylation, 3-
hydroxylationCYP2C9, CYP3A4,
CYP2C19Sai et al., 2000
Dibenzylfluorescein Fluorescent CYP probe O-debenzylation CYP3A4, CYP2C19,CYP2C9, CYP3A5,CYP3A7
Miller et al., 2000
Diclofenac Anti-inflammatory, NSAID 49-hydroxylation, 5-hydroxylation
CYP2C9, CYP3A4,CYP2C18/19
Mancy et al., 1999
Diltiazem Antihypertensive, CCB N-demethylation CYP3A4, CYP2C9, CYP2D6 Sutton et al., 1997Docetaxel Anticancer, taxane Baccatin ring hydroxylation CYP3A4 Komoroski et al., 2005Dovitinib Anticancer, PKI CYP1A1/2, CYP2D6,
CYP3A4Kim et al., 2011c
DY-9760e Calmodulin antagonist Imidazole oxidation (M8),N-dealkylation (DY-9836), O-demethylation(M5), phenylhydroxylation (M3)
CYP3A4, CYP2C9,CYP2C19
Tachibana et al., 2005
Eltrombopag Antihemorrhagic, c-mplreceptor agonist
Monooxygenation (J andM6)
CYP1A2 FDA, 2008c
Elzasonan Antidepressant N-demethylation (M4) CYP3A4 Kamel et al., 2013Erlotinib Anticancer, PKI CYP3A4/5, CYP1A2,
CYP1A1, CYP1B1FDA 2004; Ling et al., 2006
Ethanol Alcohol, solvent Acetaldehyde formation CYP2E1, CYP1A2 Hamitouche et al., 2006Etodolac Anti-inflammatory, NSAID 6-hydroxylation, 7-
hydroxylationCYP2C9 Tougou et al., 2004
Evatanepag (CP-533,536) Prostaglandin EP2 receptoragonist
Formation of M3, M4, M20,M22-M6
CYP3A4/5 Prakash et al., 2008
Everolimus Immunosuppressant, PKI Hydroxylation CYP3A4/5 Jacobsen et al., 2001;Picard et al., 2011
Febuxostat Antihyperuricemic, XOinhibitor
Hydroxylation (67M-2) CYP1A2, CYP2C9 Mukoyoshi et al., 2008;FDA, 2009c
Felodipine Antihypertensive, CCB CYP3A4 Karlsson et al., 2013Flutamide Anticancer, antiandrogen Flu-1-G2 formation CYP1A2, CYP3A4, CYP2C9 Kang et al., 2008Fluvastatin (acid, parent) Antihyperlipidemic, HMG-
CoA reductase inhibitor5-hydroxylation CYP2C9, CYP1A1,
CYP2D6, CYP3A4Fischer et al., 1999
Gallopamil Antiarrhythmic, CCB Oxidation CYP3A4, CYP2D6 Suzuki et al., 1999Genistein Anticancer, PKI 39-hydroxylation CYP1A2, CYP2E1 Hu et al., 2003Gliclazide Antidiabetic, sulfonylurea 6b-hydroxylation, 7b-
hydroxylationCYP2C9, CYP2C19 Elliot et al., 2007
Glyburide(glibenclamide)
Antidiabetic, sulfonylurea 4-trans- (M1) and 3-cis-hydroxycyclohexyl (M2b)glyburide formation
CYP3A4, CYP2C9, CYPC19 Zharikova et al., 2009
Halofantrine Antimalarial N-debutylation CYP3A4/5 Baune et al., 1999Ibrolipim (NO-1886) Antihyperlipidemic O-deethylation (M2) CYP3A4 Morioka et al., 2002ID951551 Acotiamide analog Deisopropylation CYP3A4, CYP1A1 Furuta et al., 2004Ifosfamide Anticancer, alkylating
agent4-hydroxylation CYP2C9, CYP2A6,
CYP2B6, CYP3A4Chang et al., 1993; Huang
et al., 2000IN-1130 Anticancer, PKI M1 and M3 formation CYP3A4, CYP2D6,
CYP2C19Kim et al., 2008
K11777 Antiparasitic, cysteineprotease inhibitor
Formation of N-oxide CYP3A4 Jacobsen et al., 2000ab-hydroxy-homoPhe and N-
demethyl metabolitesKarenicetin Anticancer CYP3A4, CYP2D6 Smith et al., 2003L-775,606 Antimigraine, triptan Hydroxylation (M1), N-
dealkylation (M2)CYP3A4 Prueksaritanont et al., 2000
Lansoprazole Antiulcerative, PPI 5-hydroxylation CYP2C19, CYP3A4 Pichard et al., 1995Lapatinib Anticancer, PKI O-dealkylation, N-
dealkylationCYP3A4/5, CYP2C19 FDA, 2007e; Teng et al.,
2010Licofelone Anti-inflammatory, NSAID Hydroxylation (M2 and M4) CYP2C9, CYP2C19,
CYP2D6, CYP2J2,CYP3A4
Albrecht et al., 2008
Lonafarnib Anticancer, FTI Hydroxylation (M4) CYP3A4/5, CYP1A1 Ghosal et al., 2006Macitentan Antihypertensive, ERA Depropylation CYP3A4, CYP2C9,
CYP2C19Sidharta et al., 2015
(continued )
176 Backman et al.
TABLE 1—Continued
Substrate Therapeutic Use and/orDrug Class
Metabolic Pathway(s)Catalyzed by CYP2C8
Other CYP EnzymesInvolved in Overall
MetabolismaReferences
Mavoglurant Anti-Parkinson, mGLUR5antagonist
M7 formation CYP3A4, CYP1A1 Walles et al., 2013
Methadone Analgesic, opioid N-demethylation CYP2B6, CYP3A4, CYP2D6 Iribarne et al., 1996; Wangand DeVane, 2003;Chang et al., 2011
Mirodenafil Erectogenic, PDE5inhibitor
N-dealkylation CYP3A4, CYP2D6 Lee et al., 2008
Mirtazapine Antidepressant, NaSSA N-demethylation CYP2D6, CYP1A2, CYP3A4 Störmer et al., 2000Morphine Analgesic, opioid N-demethylation CYP3A4 Projean et al., 2003bMuraglitazar Antidiabetic, PPARa, and g
agonistO-demethylation, O-
dealkylationhydroxylation, N-acetyl-imide metaboliteformation
CYP2C9, CYP2C19,CYP2D6, CYP3A4
Zhang et al., 2007a
(2)(+)-Naftopidil Antihypertensive M1-M5 formation CYP2C9, CYP2C19 Zhu et al., 2014Nalfurafine Antipruritic, opioid Decyclopropylmethylation CYP3A4, CYP2C9,
CYP2C19Ando et al., 2012
Naproxen Anti-inflammatory, NSAID O-demethylation CYP2C9, CYP1A2 Rodrigues et al., 1996,Tracy et al., 1997
Nicotine Psychostimulant 5-hydroxylation CYP2A6, CYP2B6 Yamazaki et al., 1999aNifedipine Antihypertensive, CCB CYP3A4/5 Karlsson et al., 2013Nilotinib Anticancer, PKI CYP3A4, CYP1A1/2,
CYP2J2FDA, 2007c
R/S-Norverapamil Drug metabolite O-demethylation, N-dealkylation
CYP3A4/5 Tracy et al., 1999
Odanacatib Antiosteoporotic, cathepsinK enzyme inhibitor
Methyl hydroxylation (M8) CYP3A4/5 Kassahun et al., 2014
Ombitasvir (ABT-267) Antiviral, NS5A inhibitor CYP3A4, CYP3A5 FDA, 2014kOmeprazole Antiulcerative, PPI 5-hydroxylation CYP2C19, CYP3A4 Karam et al., 1996Pafuramidine maleate
(DB289)Antiparasitic O-demethylation (M1) CYPF4 Wang et al., 2006
Pazopanib Anticancer, PKI Mono-oxygenation CYP3A4, CYP1A2 FDA, 2009dPerospirone Antipsychotic MX 1, 10-11614, CO-UK2,
and CO-UK3 formationCYP3A4, CYP2D6,
(CYP1A1)Mizuno et al., 2003;
Kitamura et al., 2005Perphenazine Antipsychotic N-dealkylation CYP1A2, CYP3A4,
CYP2C19, CYP2D6,(CYP2C18)
Olesen and Linnet, 2000
Phenazone (antipyrine) Analgesic N-demethylation, 3-hydroxylation, 4-hydroxylation
CYP3A4, CYP1A2, CYP2C9 Engel et al., 1996
Phenprocoumon Antithrombotic, VKA S-49-hydroxylation CYP2C9, CYP3A4 Ufer et al., 2004Phenytoin Antiepileptic 4-hydroxylation CYP2C9, CYP2C19 Doecke et al., 1990Piperaquine Antimalarial CYP3A4 Lee et al., 2012cPitavastatin acid Antihyperlipidemic, HMG-
CoA reductase inhibitorCYP2C9 Fujino et al., 2004
Ponatinib Anticancer, PKI CYP3A4, CYP2D6, CYP3A5 FDA, 2012eProgesterone Hormonal replacement
therapyCYP2C19, CYP3A4 Waxman et al., 1991
Propofol Anesthetic 4-hydroxylation CYP2C9, CYP1A2, CYP2B6 Guitton et al., 1998Riociguat Antihypertensive, sGC
stimulatorN-demethylation CYP1A1, CYP3A4, CYP2J2 FDA, 2013b
Rotigotine Anti-Parkinson, dopamineagonist
Desthienylethyl rotigotineformation
CYP1A2, CYP2C9, CYP3A4 FDA, 2007b
Sarizotan Antipsychotic M203, EMD148107, EMD329989, and M364dformation
CYP3A4, CYP2C9, CYP1A2 Gallemann et al., 2010
Selegiline Anti-Parkinson, MAO-Binhibitor
N-demethylation CYP2B6, CYP2C19 Hidestrand et al., 2001,Salonen et al., 2003
Semagacestat Antidementia, g-secretaseinhibitor
Benzylic hydroxylation(M3)
CYP3A4/5 Yi et al., 2010
Seratrodast Antiasthmatic, TXRA 5-methyl hydroxylation, 49-hydroxylation
CYP3A4/5, CYP2C9 Kumar et al., 1997
Sildenafil Erectogenic, PDE5inhibitor
CYP3A4, CYP2C9 Karlsson et al., 2013
Simeprevir (TMC435) Antiviral, proteaseinhibitor
M21 and M2 formation CYP3A4/5, CYP2C19 FDA, 2013h
Sipoglitazar Antidiabetic, PPARaagonist
Hydroxylation (M-II) Nishihara et al., 2012
Sirolimus Immunosuppressant Hydroxylation CYP3A4/5 Jacobsen et al., 2001Sitagliptin Antidiabetic, DPP-4
inhibitorM2 and M5 formation CYP3A4 Vincent et al., 2007
Sulfadiazine Antimicrobial N-hydroxylation CYP2C9 Winter and Unadkat, 2005
(continued )
Role of CYP2C8 in Drug Metabolism and Interactions 177
docetaxel at high concentrations was metabolized byCYP2C8, but no enzyme kinetic parameters weredetermined (Komoroski et al., 2005). An earlierstudy, however, suggested that CYP2C8 is unable toaccommodate docetaxel in its active site because ofthe absence of a side chain in the docetaxel mole-cule (Cresteil et al., 2002). The side chain, which ispresent in the paclitaxel molecule, is required fora correct orientation of it into the active site ofCYP2C8.
The androgen receptor antagonist enzalutamide, in-dicated for treatment of castration-resistant prostatecancer, is mainly metabolized by CYP2C8 and CYP3A4/5 to enzalutamideM6 in vitro (FDA, 2012k). Then,M6 isfurthermetabolized by CYP2C8 to the activemetaboliteN-demethyl enzalutamide (M2), which accounts forapproximately 50% of the total drug exposure inplasma. CYP2C8 seems to be the predominant enzymeinvolved in enzalutamide pharmacokinetics also in vivo(section VI.C.5; Gibbons et al., 2015).
TABLE 1—Continued
Substrate Therapeutic Use and/orDrug Class
Metabolic Pathway(s)Catalyzed by CYP2C8
Other CYP EnzymesInvolved in Overall
MetabolismaReferences
Sunitinib Anticancer, PKI N-deethylation CYP3A4, CYP2B6,CYP2C9/19
FDA, 2006b
T-5 Erectogenic, PDE5inhibitor
N-oxidation CYP3A5 Li et al., 2014a
Tacrolimus Immunosuppressant,calcineurin inhibitor
CYP3A4/5 Karlsson et al., 2013
Tamoxifen Anticancer, SERM M-I formation CYP3A4/5, CYP2D6 Desta et al., 2004Tamoxifen N-oxide Drug metabolite Reduction to tamoxifen CYP2A6, CYP1A1, CYP3A4 Parte and Kupfer, 2005Tegafur Anticancer, prodrug 5-hydroxylation CYP1A2, CYP2A6 Komatsu et al., 2000b, 2001Temazepam Sedative, benzodiazepine N-demethylation Yang et al., 1998Terbinafine Antifungal N-demethylation, side
chain oxidationCYP2C9, CYP1A2, CYP3A4 Vickers et al., 1999
Testosterone Hormonal replacementtherapy
CYP3A4/5, CYP2B6 Waxman et al., 1991
Tienilic acid Diuretic 5-hydroxylation CYP2C9 Lopez Garcia et al., 1993;Bonierbale et al., 1999
Tipifarnib Anticancer, FTI CYP3A4, CYP2C19,CYP2A6, CYP2D6,CYP2C9
Perez-Ruixo et al., 2006
R-Tofisopam Anxiolytic M3 formation CYP3A4, CYP2C9,(CYP3A5, CYP2C19)
Cameron et al., 2007
Tolbutamide Antidiabetic, sulfonylurea p-methyl hydroxylation CYP2C9, CYP2C19 Relling et al., 1990;Veronese et al., 1993;Rettie et al., 1994;Komatsu et al., 2000a
Torsemide (torasemide) Diuretic Methyl hydroxylation CYP2C9 Miners et al., 2000; Onget al., 2000
Trabectedin Anticancer N-demethylation CYP3A4, CYP2D6 Vermeir et al., 2009Tretinoin (all-trans-
retinoic acid)Antiacne, retinoid 4-hydroxylation,
18-hydroxylation,5,6-epoxy metaboliteformation
CYP26A1, CYP3A4/5,CYP2B6, CYP1A2,CYP26, CYP2C9
Leo et al., 1989; Nadin andMurray, 1999; Marillet al., 2000; Thatcheret al., 2010
Trimethadione(troxidone)
Antiepileptic N-demethylation CYP2E1, CYP3A4, CYP2C9 Kurata et al., 1998
Vanoxerine Antiarrhythmic, DRI CYP3A4, CYP2E1 Cherstniakova et al., 2001R-Warfarin Antithrombotic, VKA 4-hydroxylation,
7-hydroxylationCYP3A4, CYP1A1,
CYP2C19, CYP1A2Scordo et al., 2002; Kim
et al., 2012Vitamin A (retinol) Anti-acne, retinoid Hydroxylation CYP1A1, CYP1A2,
CYP1B1, CYP2D6,CYP3A4
Leo et al., 1989
Vortioxetine Antidepressant, SMS Sulfoxide (M4a) formation CYP2D6, CYP3A4/5,CYP2C19, CYP2C9,CYP2A6
FDA, 2013j; Chen et al.,2014
Zidovudine Antiviral, NRTI Reduction CYP2C9 Eagling et al., 1994
5-HT, 5-hydroxytryptamine (serotonin); 5-MeO-DIPT, 5-methoxy-N,N-diisopropyltryptamine; 9cUAB30, (2E,4E,6Z,8E)-8-(39,4’-dihydro-1’(2’H)-naphthalen-1’-ylidene)-3,7-dimethyl-2,4,6- octatrienoic acid; ARB, angiotensin II receptor blocker; ATP, adenosine triphosphate; BYZX, [(E)-2-(4-((diethylamino)methyl)benzylidene)-5,6-dimethoxy-2,3-dihydroinden-one];CCB, calcium channel blocker; Compound A, [(+)-(5S,6R,7R)-2-isopropylamino-7-[4-methoxy-2-((2R)-3-methoxy-2-methylpropyl)-5-(3,4-methylenedioxyphenyl) cyclopenteno[1,2-b]pyridine 6-carboxylic acid]; DPP, dipeptidyl peptidase; DRI, dopamine reuptake inhibitor; DY-9760, 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate; ERA, endothelin receptor antagonist; FTI, farnesyl transferase inhibitor; GABA, g-aminobutyric acid; HMG-CoA,3-hydroxy-3-methylglutaryl-coenzyme A; IN-1130, 3-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide; K11777, N-methyl-piperazine-Phe-homoPhe-vinylsulfone-phenyl; L-775,606, (1-(3-(5-(1,2, 4-triazol-4-yl)-1H-indol-3-yl)propyl)-4-(2-(3-fluorophenyl)ethyl)piperazine); LABA, long-acting b-adrenoceptor agonist; LTRA,leukotriene receptor antagonist; MAO, monoamine oxidase; mGLUR, metabotropic glutamate receptor; c-mpl, myeloproliferative leukemia; NaSSA, noradrenergic andspecific serotonergic antidepressant; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside analog reverse transcriptase inhibitor; NS, nonstructuralprotein; NSAID, nonsteroidal anti-inflammatory drug; PDE, phosphodiesterase; PGD2, prostaglandin D2; PKI, protein kinase inhibitor; PPAR, peroxisome proliferator-activated receptor; PPI, proton pump inhibitor; sGC, soluble guanylate cyclase; SERM, selective estrogen receptor modulator; SMS, serotonin modulator andstimulator; SSRI, selective serotonin reuptake inhibitor; STS, steroid sulfatase; T-5, methyl 2-(4-aminophenyl)-1-oxo-7-(pyridin-2-ylmethoxy)-4-(3,4,5-trimethox-yphenyl)-1,2-dihydroisoquinoline-3-carboxylate; TCA, tricyclic antidepressant; TXRA, thromboxane A2 receptor antagonist; VKA, vitamin K antagonist; XO, xanthineoxidase.
aThis information is either based on the references given in the table or on data from the UW Metabolism and Transport Drug Interaction Database (DIDB), CopyrightUniversity of Washington 1999-2015 (DIDB Accessed May-September, 2015).
178 Backman et al.
Several protein kinase inhibitors are metabolizedby CYP2C8 to various degrees in vitro (Table 1). Invitro, the majority (60–70%) of dabrafenib, a selectiveBRAF inhibitor, is metabolized by CYP2C8, and asmaller part by CYP3A4 (;25%) and CYP2C9 (#10%)(Lawrence et al., 2014). Recombinant CYP2C8 pro-duced only hydroxydabrafenib, whereas CYP3A4 formedboth hydroxydabrafenib and carboxydabrafenib. How-ever, the in vivo importance of CYP2C8 in dabrafenibpharmacokinetics seems to be quite modest (section VI.C.5; Suttle et al., 2015). Imatinib, the first tyrosinekinase inhibitor approved for clinical use, is metabo-lized by several CYP enzymes in vitro, with CYP2C8and CYP3A4 being the most important ones (Nebotet al., 2010; Filppula et al., 2013a). CYP3A4 is involvedin several metabolic pathways of imatinib, whereas
CYP2C8 only catalyzes the formation of the mainmetabolite, N-demethylimatinib (Table 4; Rochat et al.,2008; Filppula et al., 2013a). The relative roles ofCYP2C8 and CYP3A4 in the in vivo pharmacokineticsof imatinib are complex (section VI.C.5; Filppula et al.,2013b). In vitro, the multitargeted tyrosine kinaseinhibitor ponatinib is mainly metabolized by CYP3A4,followed by CYP2C8, CYP2D6, and CYP3A5. The con-tributions of CYP3A4 and CYP2C8 to the in vivoelimination of ponatinib are estimated to 34% and 19%,respectively (FDA, 2012e). Furthermore, CYP2C8 playsa major role in theN-demethylation of the aurora kinaseinhibitor tozasertib (Table 4; Ballard et al., 2007). Withthe exception of dabrafenib and imatinib, the in vivoimportance of CYP2C8 in the metabolism of proteinkinase inhibitors seems to have been poorly studied.
TABLE 2Glucuronide metabolites that are metabolized by CYP2C8
Substrate Metabolic pathwaycatalyzed by CYP2C8
Other CYP enzymes involvedin overall metabolism References
Clopidogrel acyl 1-b-D-glucuronidea Tornio et al., 2014Desloratadine N-glucuronide 3-hydroxylation Kazmi et al., 2015Diclofenac acyl glucuronide 49-hydroxylation Kumar et al., 2002Estradiol-17b-glucuronide 2-hydroxylation CYP3A7 Delaforge et al., 2005Gemfibrozil 1-O-b glucuronide Benzylic oxidation Ogilvie et al., 2006; Baer et al., 2009Licofelone 1-O-acyl glucuronide (M1) Hydroxylation (M3) Albrecht et al., 2008Lu AA34893 carbamoyl glucuronidea Kazmi et al., 2010MRL-C acyl glucuronide Hydroxylation CYP3A4 Kochansky et al., 2005Sipoglitazar b-1-O-acyl glucuronide O-dealkylation (M-I) Nishihara et al., 2012
MRL-C, 2-[[5,7-dipropyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy]-2-methylpropanoic acid.aThese glucuronides are likely to be substrates of CYP2C8 based on their metabolism-dependent inhibitory effect on CYP2C8.
TABLE 3Natural and endogenous compounds that are metabolized by CYP2C8
Substrate Description Metabolic Pathway(s)Catalyzed by CYP2C8
Other CYP Enzymes Involvedin Overall Metabolisma References
1-Hydroxyl-2,3,5-trimethoxyxanthone Constituent ofHalenia elliptica
M1-M4 formation CYP3A4, CYP1A2,CYP2A6, CYP2B6,CYP2C9, CYP2C19
Feng et al., 2014
7a- and 7b-Hydroxy-D8-THC Marijuana constituent Oxidation CYP3A4, CYP2C9 Watanabe et al., 20078-Prenylnaringenin (flavaprenin) Prenylflavonoid M2 formation CYP2C19 Guo et al., 2006Arachidonic acid Endogenous
compoundCYP2C9, CYP1A2,
CYP2E1, CYP2J2Daikh et al., 1994; Rifkind
et al., 1995; Zeldin et al.,1995; Barbosa-Sicard et al.,2005
Eicosapentaenoic acid Endogenouscompound
CYP2C9/11/23 Barbosa-Sicard et al., 2005
Eupatilin Flavone 4-O-demethylation CYP1A2 Lee et al., 2007R/S-Limonene Terpene CYP2C19, CYP2C9,
CYP3A4Miyazawa et al., 2002
Magnolin Constituent of Shin-i O-demethylation(M1 and M2),hydroxylation (M4)
CYP2C9, CYP2C19,CYP3A4
Kim et al., 2011a
Mesaconitine Alkaloid M1-M2, M7-M9formation
CYP3A4, CYP2C9,CYP2D6
Ye et al., 2011
Nitidine chloride Alkaloid CYP3A4 Li et al., 2014bSilybin (silibinin) Flavonolignan O-demethylation (CYP3A4) Jancova et al., 2007Tanshinol borneol ester Combination of the
natural compoundsdanshensu andborneol
M1-M5 formation (CYP3A4) Liu et al., 2010b
THC, tetrahydrocannabinol.aThis information is either based on the references given in the table or on data from the UW Metabolism and Transport Drug Interaction Database (DIDB), Copyright
University of Washington 1999-2015 (DIDB Accessed May-September, 2015).
Role of CYP2C8 in Drug Metabolism and Interactions 179
TABLE 4CYP2C8-mediated reactions in vitro
Substrate Metabolic Pathway Km Vmax CLinta Test System References
mM pmol/min/pmol(pmol/min/mg)
ml/min/pmol(ml/min/mg)
5-MeO-DIPT (Foxy) N-deisopropylation 291 1.7 0.0058 rCYP2C8 Narimatsu et al., 20067-Epi-10-deacetyl-
paclitaxelHydroxylation 18.0 3.038 0.17 rCYP2C8 Zhang et al., 2009a
7-Epi-cephalomannine M-2 formation 2.6 1.882 0.72 rCYP2C8 Zhang et al., 2009a7-Epi-paclitaxel M-2 formation 1.4 1.409 1.0 rCYP2C8 Zhang et al., 2009b8-prenylnaringenin M2 formation 3.72 4.64 1.3 rCYP2C8 Guo et al., 200617a-ethinylestradiol 2-hydroxylation 12 0.064 0.0053 rCYP2C8 Wang et al., 2004Acotiamide (Z-338) Deisopropylation 152 (12.7) (0.084) rCYP2C8 Furuta et al., 2004
318 (347) (1.19) HLM Furuta et al., 2004Alitretinoin (9-cis-retinoic
acid)4-hydroxylation 7 0.948 0.14 rCYP2C8 Marill et al., 2002
Aminophenazone(aminopyrine)
N-demethylation 5,300 188 0.035 rCYP2C8 Niwa et al., 1999
Amiodarone N-deethylation 8.6 2.3 0.27 rCYP2C8 Ohyama et al., 20005.22 (12.2) (2.3) rCYP2C8 Soyama et al., 2002
Amitriptyline N-demethylation 0.072 rCYP2C8 Venkatakrishnan et al.,2001
Amodiaquine N-deethylation 0.9-1.2 2.6-3.9 2.1-4.4 rCYP2C8 Li et al., 20022.4 (1,462) (610) HLM Li et al., 20020.728 11.2 15 rCYP2C8 Walsky and Obach, 20041.89 (1,480) (780) HLM Walsky and Obach, 20040.81 0.23 0.28 rCYP2C8 Parikh et al., 20071 11 11 rCYP2C8 O’Donnell et al., 20071.95 6.87b 3.5b rCYP2C8 Baer et al., 20091.6 (9,130) (5,700) HLM Perloff et al., 20093.0 5.7b 1.9b rcCYP2C8 Kaspera et al., 2011
3.33-5.17 (1,180-2,770) (220-830) HLM Sjogren et al., 20123.9-7.3 (791-861) (120-200) HLM Yang et al., 2012
1.9 (2,196) (1,200) HLM Misaka et al., 20131.8 (7.3) (4.1) HIM Misaka et al., 2013
58.8 3,234c 55c Hep Kosugi et al., 20140.22-42.44 19.91-1,140c 24-95c Hep Li and Schlicht, 2014
Anastrozole Hydroxylation 86.8 0.00005 ,0.001 rCYP2C8 Kamdem et al., 2010Arachidonic acid Total oxidative
metabolism6.0 4.6d 0.77d rCYP2C8 Barbosa-Sicard et al., 2005
Epoxidation 71 0.078 0.0011 rCYP2C8 Lundblad et al., 2005Atorvastatin (acid, parent) p-hydroxylation 35.9 0.29 0.0081 rCYP2C8 Jacobsen et al., 2000bBedaquiline N-demethylation 13.1 rCYP2C8 Liu et al., 2014Buprenorphine N-dealkylation 12.4 (176.3) (14) rCYP2C8 Picard et al., 2005Buspirone Total oxidative metabolism 0.073 rCYP2C8 Karlsson et al., 2013BYZX N-deethylation (M3) 62.1 0.099e 0.0016e rCYP2C8 Yu et al., 2013aBYZX M2 N-deethylation (M1) 143.2 (0.000370) (,0.001) rCYP2C8 Yu et al., 2013aCaffeine 1-N-demethylation 920 0.014 ,0.001 rCYP2C8 Kot and Daniel, 2008
3-N-demethylation 200 0.016 ,0.001 rCYP2C8 Kot and Daniel, 20087-N-demethylation 3,560 0.172 ,0.001 rCYP2C8 Kot and Daniel, 2008C-8-hydroxylation 3,370 0.319 ,0.001 rCYP2C8 Kot and Daniel, 2008
Carbamazepine 10,11-epoxidation 757 0.669 ,0.001 rCYP2C8 Cazali et al., 2003Cephalomannine 6a-hydroxylation 41.3 5.267 0.13 rCYP2C8 Zhang et al., 2009aCerivastatin (acid, parent) 6-hydroxylation 23 0.22 0.0096 rcCYP2C8 Kaspera et al., 2010
Demethylation 24 0.57 0.024 rcCYP2C8 Kaspera et al., 2010Cerlapirdine Demethylation 3.3 3.4 1.0 rCYP2C8 Tse et al., 2014Chloroquine N-deethylation 430 52.1 0.12 rCYP2C8 Kim et al., 2003
111 8.33 0.075 rCYP2C8 Projean et al., 2003aCilostazol OPC-13217 formation 33.8 0.30 0.089 rCYP2C8 Hiratsuka et al., 2007Cisapride 4-hydroxylation ;5.9 0.71 ;0.12 rCYP2C8 Desta et al., 2000
N-dealkylation ;0.91 0.29 ;0.32 rCYP2C8 Desta et al., 20002-hydroxylation 5.80 0.0267 0.0046 rCYP2C8 Pearce et al., 20014-hydroxylation 3.40 0.289 0.085 rCYP2C8 Pearce et al., 2001N-dealkylation 2.0 0.109 0.055 rCYP2C8 Pearce et al., 2001
(2)-Cisapride 4-hydroxylation 13.3 0.15 0.011 rCYP2C8 Desta et al., 2001(+)-Cisapride 4-hydroxylation 12.6 0.24 0.019 rCYP2C8 Desta et al., 2001Cyclosporine Total oxidative metabolism 0.40 rCYP2C8 Karlsson et al., 2013Dapsone N-hydroxylation 58-75 0.440 0.0059-0.0076 rCYP2C8 Winter et al., 2000Dibenzylfluorescein O-debenzylation 1.0 0.4d 0.4d n/a Miller et al., 2000
29.16 0.79 0.027 rCYP2C8 Ghosal et al., 20031.9 (1.3) (0.68) THLE Donato et al., 2004
Diclofenac 49-hydroxylation 630 1.2b,d 0.0019b,d rCYP2C8 Mancy et al., 19995-hydroxylation 280 7b,d 0.025b,d rCYP2C8 Mancy et al., 1999
DY-9760e Imidazole oxidation (M8) 2.6 0.0732 0.028 rCYP2C8 Tachibana et al., 2005N-dealkylation (DY-9836) 15.2 0.0231 0.0015 rCYP2C8 Tachibana et al., 2005O-demethylation (M5) 3.1 0.0128 0.0041 rCYP2C8 Tachibana et al., 2005Phenyl hydroxylation (M3) 2.5 0.2955 0.12 rCYP2C8 Tachibana et al., 2005
(continued )
180 Backman et al.
TABLE 4—Continued
Substrate Metabolic Pathway Km Vmax CLinta Test System References
Eicosapentaenoic acid Total oxidative metabolism 5.4 6.2d 1.1d rCYP2C8 Barbosa-Sicard et al., 2005Estradiol-17b-glucuronide 2-hydroxylation 88 1.86 0.021 rCYP2C8 Delaforge et al., 2005Ethanol Acetaldehyde formation 8,300 (0.0043) (,0.001) rCYP2C8 Hamitouche et al., 2006Eupatilin 4-O-demethylation 4.5 0.94 0.21 rCYP2C8 Lee et al., 2007Felodipine Total oxidative metabolism 1.1 rCYP2C8 Karlsson et al., 2013Fenretidine 49-hydroxylation 2.2 282f 130f rCYP2C8 Illingworth et al., 2011
49-oxidation 5.0 30f 6.0f rCYP2C8 Illingworth et al., 2011R-Fluoxetine N-demethylation 153.8 (6.08) (0.040) rcCYP2C8 Wang et al., 2014bS-Fluoxetine N-demethylation 195.0 (6.68) (0.034) rcCYP2C8 Wang et al., 2014bFluvastatin (acid, parent) 5-hydroxylation 2.8 0.13 0.046 rCYP2C8 Fischer et al., 1999Gliclazide 6b-hydroxylation 984 0.63 ,0.001 rCYP2C8 Elliot et al., 2007
7b-hydroxylation 346 0.06 ,0.001 rCYP2C8 Elliot et al., 2007Glyburide (glibenclamide) Total oxidative metabolism 10.2 0.9 0.09 rCYP2C8 Zharikova et al., 2009
7.7 2.5 0.32 rCYP2C8 Zhou et al., 20100.08 rCYP2C8 Varma et al., 2014
Halofantrine N-debutylation 156 0.039 ,0.001 rCYP2C8 Baune et al., 1999Ibrolipim (NO-1886) O-deethylation (M2) 28.4–53.9 0.0334–0.10 0.0012–0.0019 rCYP2C8 Morioka et al., 2002R-Ibuprofen 2-hydroxylation 3.5–74 rCYP2C8 Hamman et al., 1997
282 9.4 0.033 rCYP2C8 Chang et al., 2008341.3 4.92e 0.014e rCYP2C8 Yu et al., 2013b
S-Ibuprofen 2-hydroxylation 292 5.4 0.018 rCYP2C8 Chang et al., 2008388.8 3.02e 0.0078e rCYP2C8 Yu et al., 2013b
Imatinib N-demethylation 1.4 0.408 0.29 rCYP2C8 Nebot et al., 20104.28 4.07 0.95 rCYP2C8 Filppula et al., 2013a5 0.553 0.1 rCYP2C8 Khan et al., 2015
Isotretinoin (13-cis-retinoicacid)
4-hydroxylation 13.8 134.6g 9.8g rCYP2C8 Rowbotham et al., 2010
L-775,606 Hydroxylation (M1) 42 0.62 0.015 rCYP2C8 Prueksaritanont et al., 2000N-dealkylation (M2) 64 0.03 ,0.001 rCYP2C8 Prueksaritanont et al., 2000
Loperamide N-demethylation 11.3 0.0052 ,0.001 rCYP2C8 Kim et al., 2004Magnolin O-demethylation (M1) 17.7 1.9 0.11 rCYP2C8 Kim et al., 2011a
O-demethylation (M2) 21.2 0.3021 0.014 rCYP2C8 Kim et al., 2011aHydroxylation (M4) 29.7 0.7099 0.024 rCYP2C8 Kim et al., 2011a
Mavoglurant Total oxidative metabolism 17.1 5.06 0.30 rCYP2C8 Walles et al., 2013Mirodenafil N-dealkylation (SK3541) 121 0.85 0.0070 rCYP2C8 Lee et al., 2008Montelukast 36-hydroxylation (M6) 0.050 0.18 3.6 rCYP2C8 Filppula et al., 2011
0.014 ;0.24 ;17 rCYP2C8 VandenBrink et al., 20110.065 ;0.09 ;1 HLM VandenBrink et al., 20110.31 0.015 0.048 rCYP2C8 Oliveira Cardoso et al.,
201525-hydroxylation (M3) 0.33 0.002 0.006 rCYP2C8 Oliveira Cardoso et al.,
2015Morphine N-demethylation 4,800 5.41 0.0011 rCYP2C8 Projean et al., 2003bNifedipine Total oxidative metabolism 0.38 rCYP2C8 Karlsson et al., 2013Nitidine chloride Total oxidative metabolism 1.17 0.0705 0.060 rCYP2C8 Li et al., 2014bR-Norverapamil D-620 formation 56 5.3 0.095 rCYP2C8 Tracy et al., 1999
PR-22 formation 38 29 0.76 rCYP2C8 Tracy et al., 1999S-Norverapamil D-620 formation 80 14 0.18 rCYP2C8 Tracy et al., 1999
PR-22 formation 80 12 0.15 rCYP2C8 Tracy et al., 1999Olanzapine N-demethylation 30 1.370 0.046 rCYP2C8 Korprasertthaworn et al.,
2015Omeprazole 5-hydroxylation 300 3.3 0.011 rCYP2C8 Karam et al., 1996Paclitaxel 6a-hydroxylation 5.4 30 5.6 rCYP2C8 Rahman et al., 1994
4.0 (870) (220) HLM Rahman et al., 199415 0.12 0.0080 HLM Monsarrat et al., 199717 HLM Ando et al., 199826 HLM Desai et al., 199834.8 (1632) (47) HLM Fischer et al., 19984.9 1.14 0.23 rCYP2C8 Masimirembwa et al., 19996 (234) (39) rCYP2C8 Ong et al., 2000
12.2 (142) (12) HLM Ong et al., 20002.85 5.667 2.0 rCYP2C8 Ohyama et al., 2000
2.58–4.55 0.224–0.583 0.070–0.19 HLM Ohyama et al., 20006.8 3.0d 0.44d rCYP2C8 Yamazaki et al., 2000
15 0.8 0.053 rCYP2C8 Dai et al., 20014.3 (147) (34) rCYP2C8 Fujino et al., 2001
27.4 (359) (13) HLM Fujino et al., 200116.2 29.8 1.8 rCYP2C8 Soyama et al., 200115 1.950 0.13 HLM Cresteil et al., 20029.3 (60.9) (6.8) HLM Václavíková et al., 2003
13.3 (109.1) (8.2) HLM Donato et al., 200416.3 (81.0) (5.0) THLE Donato et al., 20047.50 (70.2) (9.4) HLM Polasek et al., 20048.3 1.718 0.21 rCYP2C8 Zhang et al., 2009b
18.3 (250) (14) HLM Zhang et al., 2009b
(continued )
Role of CYP2C8 in Drug Metabolism and Interactions 181
TABLE 4—Continued
Substrate Metabolic Pathway Km Vmax CLinta Test System References
4.17 2.4 0.58 rCYP2C8 Gao et al., 20102.33 4.05 1.7 rCYP2C8 Hanioka et al., 20103.7 0.29b 0.078b rcCYP2C8 Kaspera et al., 20112.58 3.53 1.4 rCYP2C8 Wattanachai et al., 20117.08 (137) (19) HLM Wattanachai et al., 20118.65 69.83 8.1 rCYP2C8 Yu et al., 2013b5.2 (222.1) (43) HLM Wang et al., 2014a
5.41–15.9 (52.6–230) (3.3–26) HLM Kudo et al., 2015Pafuramidine maleate
(DB289)O-demethylation (M1) 2.6 0.12 0.046 rCYP2C8 Wang et al., 2006
Perospirone Total oxidative metabolism 1.09 1.93 1.8 rCYP2C8 Kitamura et al., 2005Perphenazine N-dealkylation 28 1.35 0.048 rCYP2C8 Olesen and Linnet, 2000Phenazone (antipyrine) N-demethylation 30,400 (156.4) (0.0051) rCYP2C8 Engel el al., 1996
3-hydroxylation 22,000 (43.9) (0.0020) rCYP2C8 Engel el al., 19964-hydroxylation 61,000 (140.9) (0.0023) rCYP2C8 Engel el al., 1996
Phenprocoumon S-49-hydroxylation 3.78 0.027 0.0071 rCYP2C8 Ufer et al., 2004Pioglitazone M-IV formation 10.2 9.2 0.91 rCYP2C8 Tornio et al., 2008b
9.8 (640) (65) HLM Tornio et al., 2008b29.5 1.702 0.058 rCYP2C8 Muschler et al., 2009
R483 Hydroxylation (M1) 1.4 (1,000) (700) n/a Bogman et al., 2010Repaglinide Total oxidative metabolism 2.8 4.9 1.8 rCYP2C8 Kajosaari et al., 2005a
M1 formation 25 0.08 0.003 rCYP2C8 Säll et al., 2012M4 formation 5.7 0.35 0.061 rCYP2C8 Säll et al., 2012M4 formation 9.0 (130) (14) HLM Säll et al., 2012M4 formation 28 13c 0.46c Hep Säll et al., 2012M4 formation 13 (18) (1.4) S9 Säll et al., 2012
12.01 15.69e 1.3e rCYP2C8 Yu et al., 2013bRosiglitazone p-hydroxylation 44 (2,900) (66) rCYP2C8 Baldwin et al., 1999
4.3–7.7 (550–883) (93–130) HLM Baldwin et al., 1999N-demethylation 10 (2,430) (240) rCYP2C8 Baldwin et al., 1999p-hydroxylation 4.0 0.42b 0.11b rcCYP2C8 Kaspera et al., 2011N-demethylation 2.9 0.38b 0.13b rcCYP2C8 Kaspera et al., 2011
Selegiline Demethylation 82 3 0.04 rCYP2C8 Hidestrand et al., 2001Levomethamphetamine
formation630 7 0.01 rCYP2C8 Hidestrand et al., 2001
Seratrodast 49-hydroxylation 28.2 0.1438 0.0051 rCYP2C8 Kumar et al., 19975-methylhydroxylation 32.9 0.4983 0.015 rCYP2C8 Kumar et al., 1997
Sildenafil Total oxidative metabolism 0.055 rCYP2C8 Karlsson et al., 2013Simvastatin acid M1 formation 88 2,800 32 rCYP2C8 Prueksaritanont et al., 2003
M2 formation 36 850 24 rCYP2C8 Prueksaritanont et al., 2003M3 formation 16 600 38 rCYP2C8 Prueksaritanont et al., 2003
T-5 N-oxidation 1.6 0.22 0.14 rCYP2C8 Li et al., 2014aTacrolimus Total oxidative metabolism 0.19 rCYP2C8 Karlsson et al., 2013Tanshinol borneol ester M3 formation 45.2 4.28h 0.095h rCYP2C8 Liu et al., 2010bTerbinafine Deamination 24.8 0.512 0.021 rCYP2C8 Vickers et al., 1999
N-demethylation 13.6 2.06 0.15 rCYP2C8 Vickers et al., 1999Side chain oxidation 26.4 0.825 0.031 rCYP2C8 Vickers et al., 1999Total oxidative metabolism 15.3 4.47 0.29 rCYP2C8 Vickers et al., 1999
R-Tofisopam M3 formation 52 0.43 0.0083 rCYP2C8 Cameron et al., 2007Tolbutamide Hydroxylation 650.5 rCYP2C8 Veronese et al., 1993
531 0.39 ,0.001 rCYP2C8 Rettie et al., 19941,160 (10.2) (0.0088) rCYP2C8 Pang et al., 2012
Torsemide (torasemide) Methyl hydroxylation 184 1.8 0.0098 rCYP2C8 Miners et al., 2000170 (35) (0.21) rCYP2C8 Ong et al., 2000
Tozasertib (MK 0457, VX6,VX 680)
N-demethylation 64 129 2.0 rCYP2C8 Ballard et al., 2007
Tretinoin (all-trans-retinoicacid)
4-hydroxylation 6.1 0.18 0.030 rCYP2C8 Nadin and Murray, 1999
4-hydroxylation 50 1.211 0.024 rCYP2C8 Marill et al., 200018-hydroxylation 17 0.033 0.0019 rCYP2C8 Marill et al., 20005,6-epoxy metabolite
formation130 0.450 0.0035 rCYP2C8 Marill et al., 2000
4-hydroxylation 13.4 4.8 0.36 rCYP2C8 Thatcher et al., 2010Troglitazone Quinone formation 2.7 4.2d 1.6d rCYP2C8 Yamazaki et al., 1999bVerapamil O-demethylation 48.4 (13) (0.27) rCYP2C8 Busse et al., 1995
Total oxidative metabolism 0.39 rCYP2C8 Karlsson et al., 2013R-Verapamil D-617 formation 127 8.0 0.063 rCYP2C8 Tracy et al., 1999
Norverapamil formation 127 6.9 0.054 rCYP2C8 Tracy et al., 1999PR-22 formation 33 2.2 0.067 rCYP2C8 Tracy et al., 1999
S-Verapamil D-617 formation 185 8.0 0.043 rCYP2C8 Tracy et al., 1999Norverapamil formation 154 15 0.097 rCYP2C8 Tracy et al., 1999PR-22 formation 141 1.6 0.011 rCYP2C8 Tracy et al., 1999
(continued )
182 Backman et al.
In addition, CYP2C8 participates to various degree tothe metabolism of several other anticancer agents, aslisted in Table 1.2. Antidiabetic Agents. The nonsulfonylurea insulin
secretagogue repaglinide is metabolized primarily byCYP2C8 (Table 4) and CYP3A4, but it also undergoesdirect glucuronidation by uridine-59-diphosphoglucuro-nosyltransferase (UGT) 1A1 (Bidstrup et al., 2003;Kajosaari et al., 2005a,b; Gan et al., 2010). In addition,there is in vitro data suggesting that aldehyde de-hydrogenase is involved in its metabolism (Säll et al.,2012). Moreover, repaglinide is a substrate of thehepatic uptake transporter organic anion-transportingpolypeptide (OATP) 1B1 (Niemi et al., 2005b, 2011). Theformation of the main metabolites of repaglinide, anoxidized dicarboxylic acid (M2) and, in particular, 39-hydroxyl repaglinide (M4), is largely dependent onCYP2C8, whereas the less important aromatic aminemetabolite (M1) is primarily formed by CYP3A4 (Bidstrupet al., 2003; Kajosaari et al., 2005a,b).Pioglitazone, a thiazolidinedione peroxisome prolif-
erator activated receptor (PPAR) g agonist, is primarilymetabolized by CYP2C8 in vitro, with smaller contri-butions by CYP3A4 and the extrahepatic CYP1A1(Jaakkola et al., 2006c; FDA, 2013a). In vitro, CYP2C8forms the pharmacologically active hydroxypioglita-zone (M-IV) and ketopioglitazone (M-III) (Jaakkolaet al., 2006c; Tornio et al., 2008b), which are the mainmetabolites in human serum with concentrations equalto or greater than those of the parent drug (Ecklandand Danhof, 2000). In vivo studies support the centralrole of CYP2C8 in pioglitazone metabolism observedin vitro (section VI.C.2).Rosiglitazone, another PPAR-g agonist, is also a
substrate of CYP2C8. In vitro, it undergoes CYP2C8-mediated p-hydroxylation andN-demethylation (Table 4),followed by sulfate and glucuronic acid conjugation(Baldwin et al., 1999; Kaspera et al., 2011; FDA,2014a). CYP2C9 also participates in its metabolismto a minor extent (Baldwin et al., 1999). Rosiglitazonep-hydroxylation is recommended by the Food and
Drug Administration (FDA) as a marker reaction forin vitro CYP2C8 activity (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm). In vitro,troglitazone is metabolized by CYP2C8 to its qui-none metabolite (M3) (Table 4) at a two- to eightfoldhigher rate than by CYP2C19, CYP3A4, and CYP2C9(Yamazaki et al., 1999b). M3 is a minor metabolite oftroglitazone, but it has been suggested to be responsiblefor the drug-induced hepatotoxicity associated withtroglitazone use (Yamazaki et al., 1999b; Smith,2003). Furthermore, the thiazolidinedione R483 isprimarily metabolized by CYP2C8 and CYP2C19 invitro (Bogman et al., 2010). CYP2C8 catalyzes theformation of the weakly active M1 metabolite (Table 4)and its further metabolism to M4, which is the mainmetabolite of R483 in plasma. In turn, CYP2C19 formsM2, which shows similar pharmacological activity asparent R483 (Bogman et al., 2010).
Additionally, CYP2C8 is involved, to a minor extent,in the metabolism of the sulfonylureas gliclazide,glyburide, and tolbutamide, the dipeptidyl peptidase 4inhibitor sitagliptin, and the PPARa agonist sipoglita-zar (Table 1; Relling et al., 1990; Srivastava et al., 1991;Veronese et al., 1993; Elliot et al., 2007; Vincent et al.,2007; Zharikova et al., 2009; Nishihara et al., 2012).Tolbutamide p-methyl hydroxylation has been used asa marker reaction for CYP2C8 activity in several invitro studies. However, its Michaelis-Menten constant(Km) for CYP2C8 is very high (.530 mM; Table 4), andit is effectively metabolized by CYP2C9 at lowerconcentrations.
3. Antimalarial Agents. The 4-aminoquinoline de-rivative amodiaquine, widely used for treatment ofmalaria for more than 60 years, is a substrate ofCYP2C8 (Li et al., 2002). It is also metabolized by theextrahepatic enzymes CYP1A1 and CYP1B1 to a minorextent (Li et al., 2002). Amodiaquine N-deethylation is afrequently used in vitro marker reaction for CYP2C8because of its high affinity (Km typically around 2 mM)and high turnover rate (Table 4).N-desethylamodiaquine,
TABLE 4—Continued
Substrate Metabolic Pathway Km Vmax CLinta Test System References
Vidupiprant (AMG 853) t-butyl hydroxylation (M2) 1.21 0.031 0.026 rCYP2C8 Foti et al., 2012Cyclopropyl hydroxylation
(M3)49.1 0.250 0.0051 rCYP2C8 Foti et al., 2012
Vitamin A (retinol) 4-hydroxylation 71 1.73 0.024 rcCYP2C8 Leo et al., 1989Zopiclone N-demethylation 71 2.5 0.035 rCYP2C8 Becquemont et al., 1999
N-oxidation 59 1.0 0.017 rCYP2C8 Becquemont et al., 1999
5-MeO-DIPT, 5-methoxy-N,N-diisopropyltryptamine; BYZX, [(E)-2-(4-((diethylamino)methyl)benzylidene)-5,6-dimethoxy-2,3-dihydroinden-one]; CLint, intrinsic clearance;Hep, hepatocytes; HIM, human intestinal microsomes; HLM, human liver microsomes; Km, Michaelis-Menten constant; n/a, not available; rCYP2C8, recombinant CYP2C8;rcCYP2C8, reconstituted CYP2C8; S9, S9 fraction; THLE, immortalized human liver epithelial cells; Vmax, maximal velocity.
aCalculated as Vmax/Km.bkcat reported instead of Vmax, CLint calculated as kcat/Km.cVmax as pmol/min/106 cells, CLint as pmol/min/106 cells/mM.dVmax as 1/min, CLint as 1/min/mM.eVmax as arbitrary unit (AU), CLint as AU/mM.fVmax as unit/min, CLint as unit/min/mM.gVmax as counts/s/s, CLint as counts/s/s/mM.hVmax as AUC×min/nmol, CLint as AUC×min/nmol/mM.
Role of CYP2C8 in Drug Metabolism and Interactions 183
which is the main metabolite of amodiaquine, is assumedto be the main entity responsible for the pharmacologicalresponse to amodiaquine (Churchill et al., 1985; Mountet al., 1986).Chloroquine, also a 4-aminoquinoline, is mainly
metabolized to its N-desethyl metabolite by CYP2C8(Table 4) and CYP3A4, with a small contribution byCYP2D6 in vitro (Kim et al., 2003; Projean et al., 2003a).Furthermore, CYP2C8 also seems to play a small rolein the in vitro metabolism of the antimalarial agentsdapsone, halofantrine, and piperaquine (Table 1; Bauneet al., 1999; Winter et al., 2000; Lee et al., 2012c).4. Lipid-lowering Drugs. CYP2C8 participates to a
small extent in the metabolism of several HMG-CoAreductase inhibitors (statins), but it has a major role forthe biotransformation of cerivastatin. Cerivastatin isextensively metabolized in humans (Boberg et al., 1997;Mück, 2000). Parent cerivastatin (acid) is metabolizedby CYP2C8 and CYP3A4, whereas cerivastatin lac-tone is predominantly metabolized by CYP3A4 (Boberget al., 1997; Wang et al., 2002; Fujino et al., 2004). Theformation of the major metabolite of cerivastatin,6-hydroxycerivastatin (M-23), is primarily mediated byCYP2C8, whereas both CYP2C8 and CYP3A4 producedemethylcerivastatin (M1) (Wang et al., 2002; Kasperaet al., 2010). The notorious in vivo interaction between
gemfibrozil and cerivastatin is discussed in sectionVI.C.4.
The parent simvastatin lactone is either oxidized byCYP3A4/5 or hydrolyzed to its acid form, which ispharmacologically active (Prueksaritanont et al., 1997,2003). In human liver microsomes (HLM), the metabo-lism of simvastatin acid was catalyzed primarily($80%) by CYP3A4/5, with a smaller contribution(#20%) by CYP2C8 (Prueksaritanont et al., 2003).Recombinant CYP2C8 formed all three simvastatinacid metabolites (M1-M3) observed in HLM (Table 4;Prueksaritanont et al., 2003). In vitro, fluvastatin ismainly metabolized by CYP2C9 into three metabolites,but CYP1A1, CYP2C8, CYP2D6, and CYP3A4 form5-hydroxyfluvastatin (Fischer et al., 1999). Both atorvas-tatin (acid) and its lactone are primarily metabolizedby CYP3A4 to their hydroxylated metabolites in vitro,but CYP2C8 is involved in the formation of p-hydroxyatorvastatin acid to a small extent (Jacobsen et al.,2000b). Furthermore, pitavastatin acid is metabolizedby CYP2C9 and CYP2C8 in vitro, whereas its lactone ismetabolized by CYP3A4 and CYP2D6 (Fujino et al.,2004).
5. Other Drugs. Early in vitro studies concludedthat the leukotriene receptor antagonist montelukastis mainly metabolized by CYP2C9 and CYP3A4 (Chiba
Fig. 3. Molecular descriptors of drugs classified as "major" or "intermediate" CYP2C8 substrates in Table 1. The molecular descriptors were obtainedfrom SciFinder (American Chemical Society).
184 Backman et al.
et al., 1997), whereas the role of CYP2C8 was notevaluated. However, in vitro studies performed morethan a decade later demonstrated that CYP2C8 is thekey enzyme involved in the oxidative metabolism ofmontelukast (Filppula et al., 2011; VandenBrink et al.,2011). CYP2C8 catalyzes the main metabolic pathwayof montelukast; formation of the pharmacologicallyactive 36-hydroxymontelukast (M6), and its subsequentmetabolism to the secondary metabolite M4, a dicar-boxylic acid (Table 4). In addition, CYP2C8 forms 25-hydroxymontelukast (M3) (Filppula et al., 2011). Thesein vitro findings are in agreement with X-ray crystal-lography data, demonstrating a ligand-protein bindinginteraction between montelukast and CYP2C8 (Schochet al., 2008). The montelukast molecule was positionedwith its benzyl ring in close proximity to the heme ironof CYP2C8. The montelukast metabolites M3, M4, andM6 formed by CYP2C8 in vitro, all result from theoxidation of the benzyl ring of montelukast.The novel prolyl hydroxylase inhibitor daprodustat
(GSK1278863), an antianemic agent, is primarily me-tabolized by CYP2C8, with a smaller contribution byCYP3A4 in vitro (Johnson et al., 2014). It seems tobe more sensitive than repaglinide to CYP2C8 inhibi-tion by gemfibrozil in vivo (section VI.C.8; Johnsonet al., 2014).The novel nonstructural 5B nonnucleoside polymer-
ase inhibitor dasabuvir is extensively metabolized byCYP2C8, with a small contribution by CYP3A (FDA,2014g). CYP2C8 also plays an intermediate/small rolein the metabolism of the nonstructural protein 3/4 Aprotease inhibitor paritaprevir and nonstructural pro-tein 5A inhibitor ombitasvir (FDA, 2014g; Menon et al.,2015). However, no in vitro metabolism data have yetbeen published for these compounds.The prostacyclin analog treprostinil is primarily me-
tabolized byCYP2C8, followed byCYP2C9 in vitro (FDA,
2009b). Incubation of treprostinil with recombinantCYP2C8 for 15 minutes resulted in a 95% depletion oftreprostinil concentrations, whereas only 22% was con-sumed by recombinant CYP2C9. CYP2C8 seems to be ofimportance in the in vivo pharmacokinetics of treprosti-nil (FDA, 2009b).
The sedative agent zopiclone is metabolized byCYP2C8 and CYP3A4 in vitro (Becquemont et al.,1999). In HLM, CYP2C8 was the main enzyme catalyz-ing N-demethylation of zopiclone, followed by CYP2C9and CYP3A4. CYP2C8 also participated in the forma-tion ofN-oxide zopiclone, together with CYP3A4 (major)and CYP2C9 (Becquemont et al., 1999). However, inanother in vitro study, montelukast (CYP2C8 inhibitor)and gemfibrozil (CYP2C8 and CYP2C9 inhibitor) hadno effect on the elimination of clinically relevant con-centrations of zopiclone (Tornio et al., 2006), supportingin vivo data showing a lack of effect of gemfibrozil onzopiclone concentrations in healthy subjects (sectionVI.C.8).
Based on in vitro studies, CYP2C8 likely playsan intermediate role in the elimination of 9cUAB30,alitretionin, amiodarone, cisapride, fenretinide, fluox-etine, irosustat, isotretionin, loperamide, olanzapine,olodaterol, propanoic acid, dronedarone, tazarotenicacid, verapamil, and vidupiprant (AMG 853) (Table 1).For instance, CYP2C8 catalyzes dealkylation of bothenantiomers of the calcium channel blocker verapamiland its metabolite norverapamil (Busse et al., 1995;Tracy et al., 1999). Tazarotenic acid, the activemoiety ofthe antipsoriatic agent tazarotene, is mainly metabo-lized by CYP2C8 and flavin-containing monooxyge-nases in vitro (Attar et al., 2003). When tazarotenicacid was incubated with 10 individual recombinantCYP enzymes, only CYP2C8 markedly catalyzed sul-foxidation, which is the main metabolic pathway oftazarotenic acid.
Fig. 4. The number of "major" and "intermediate" CYP2C8 substrates by drug class, as listed in Table 1.
Role of CYP2C8 in Drug Metabolism and Interactions 185
There is a vast amount of in vitro data suggesting thatCYP2C8 may be of relevance in the metabolism of anumber of other drugs (Table 1). For themajority of thesecompounds, the role of CYP2C8 in their in vivo elimina-tion is likely to be small or negligible. However, forsome drugs, the in vivo contribution of CYP2C8 to theirmetabolism cannot be estimated based on availableinformation, andmay, in fact, exceed 20%. Alternatively,CYP2C8may become a determinant in their metabolismafter inhibition of other enzymes important for theirelimination. For instance, CYP2C8 is involved in themetabolism of seratrodast, a thromboxane A2 receptorantagonist in vitro (Kumar et al., 1997). The mainmetabolic pathway of seratrodast, 5-methylhydroxylation,is primarily catalyzedbyCYP3AandCYP2C9, butCYP2C8contributes to a small degree. However, CYP2C8 is amajor contributor to seratrodast 49-hydroxylation, aminormetabolic route (Kumar et al., 1997).6. Glucuronide Metabolites. Several glucuronide me-
tabolites have been reported to undergo metabolism byCYP2C8, including clopidogrel acyl 1-b-D-glucuronide,desloratadine glucuronide, diclofenac acyl glucuronide,
estradiol-17b-glucuronide, gemfibrozil 1-O-b glucuronide,licofelone 1-O-acyl glucuronide, Lu AA34893 carbamoylglucuronide, 2-[[5,7-dipropyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy]-2-methylpropanoic acid (MRL-C)acyl glucuronide, and sipoglitazar b-1-O-acyl glucuronide(see Table 2 for references). Thus, CYP2C8 makes yetanother exception to the old concept that drugmetabolismis divided into sequential phase I and phase II reactions,i.e., functionalizationand conjugation, respectively (Fig. 5).
Kumar et al. (2002) demonstrated the first example ofCYP2C8-mediated metabolism of a glucuronide conju-gate when they showed that the conversion of diclofenacacyl glucuronide to its 49-hydroxy derivative is exclusivelymediated by CYP2C8 in vitro. In 2005, it was reportedthat CYP2C8 is also able to directly catalyze the2-hydroxylation of estradiol-17b-glucuronide in vitro(Delaforge et al., 2005). Docking of the glucuronide ofestradiol into the crystal structure of CYP2C8 showedthat the active site is large enough to inhabit theconjugate. Also the fetal CYP3A isoformCYP3A7 oxidizedestradiol-17b-glucuronide, but CYP2C8 was five timesmore active than CYP3A7. However, CYP3A4 was not
Fig. 5. Schematic illustration of the interaction between CYP2C8 and its glucuronide substrates. CYP2C8 and the UGT are localized on opposite sitesof the endoplasmic membrane (A). The drug is glucuronidated by the UGT (B). Hereafter, the glucuronide crosses the endoplasmic membrane andbinds into CYP2C8 (C). Then, the glucuronide is either metabolized by CYP2C8 and released as a metabolite (D, left), e.g., desloratadine glucuronide,and diclofenac acyl glucuronide, or it is metabolized to a reactive agent that inactivates CYP2C8 (D, right), as for clopidogrel acyl 1-b-D-glucuronide andgemfibrozil 1-O-b glucuronide. CYP2C8 has been suggested to exist as a dimer (Hu et al., (2010), Schoch et al., (2004)). ER, endoplasmic reticulum.
186 Backman et al.
able to metabolize estradiol-17b-glucuronide (Delaforgeet al., 2005). Moreover, the acyl glucuronide of the dualPPAR a/b agonistMRL-Cwas oxidized byCYP2C8 and toaminor extent byCYP3A4, but not byCYP2C9 (Kochanskyet al., 2005). Furthermore, the main elimination pathwayof licofelone, a dual inhibitor of cyclooxygenases 1 and 2and 5-lipoxygenase, is glucuronidation of its carboxylicacid metabolite, followed by CYP2C8-catalyzed hydroxyl-ation of the acyl glucuronide M1 to form the hydroxylatedglucuronide M3 (Albrecht et al., 2008).For two compounds, the formation of an unconjugated
hydroxyl metabolite involves oxidation and subsequentdeconjugation of a glucuronide metabolite. In vitro, theantidiabetic agent sipoglitazar was first glucuronidatedto sipoglitazar b-1-O-acyl glucuronide (sipoglitazar-G1).Sipoglitazar-G1 was then metabolized to the main metab-olite M-I by O-dealkylation by CYP2C8 and subsequentdeconjugation (Nishiharaet al., 2012).A similar findingwasrecently observed for desloratadine (Kazmi et al., 2015). Themain metabolite of desloratadine, 3-hydroxydesloratadine,which is active, was formed via CYP2C8-mediated oxida-tion of desloratadine glucuronide anda deconjugation event(Kazmi et al., 2015). Thus, it seems that phase II metabo-lism occurs before phase I for these compounds (Fig. 5).Also the glucuronide metabolites of clopidogrel, gem-
fibrozil, and Lu AA34893 are likely to be substrates ofCYP2C8 (Ogilvie et al., 2006; Baer et al., 2009; Kazmiet al., 2010; Tornio et al., 2014). All three compounds aremetabolism-dependent inhibitors of CYP2C8, as dis-cussed in sections V.B and VI.B.
B. Endogenous and Natural Compounds
CYP2C8 metabolizes some endogenous and natu-ral compounds (Table 3). CYP2C8 participates inthe metabolism of arachidonic acid to biologicallyactive epoxyeicosatrienoic acids (e.g., 11-, 13-, or 15-hydroxyeicosatrienoic acid), involved in the regulation ofnumerous physiologic processes, e.g., vascular function,blood pressure regulation, pancreatic peptide hormonesecretion, and platelet aggregation (Daikh et al., 1994;Rifkind et al., 1995; Zeldin et al., 1995). The roles ofCYP2C8 and other CYP enzymes in inflammation,cardiovascular disease, and cancer were recentlyreviewed by Chen andWang (2015) and Fleming (2014).CYP2C8 and CYP3A enzymes have generally been
considered to be the primary CYPs involved in themetabolism of all-trans-retinoic acid, the active form ofvitamin A (retinol) (Leo et al., 1989; Nadin and Murray,1999; Marill et al., 2000). All-trans-retinoic acid isinvolved in gene transcription, cell division, and differ-entiation (Tzimas and Nau, 2001; Marill et al., 2003;Duester, 2008). According tomore recent data, however,CYP26A1 and CYP3A4 are the primary determinants ofall-trans-retinoic acid metabolism in humans, whereasthe role of CYP2C8 is of smaller importance (Thatcheret al., 2010). In vitro, CYP2C8 also catalyzes themetabolism of other retinoids, including 9-cis-retinoic
acid, 13-cis-retinoic acid, and 9cUAB30 (Marill et al.,2002; Gorman et al., 2007).
Some in vitro data suggest that CYP2C8 may contrib-ute to the metabolism of the steroids 17b-estradiol,progesterone, and testosterone (Waxman et al., 1991;Spink et al., 1992, 1994). However, there seems to be noevidence for a role of CYP2C8 in the metabolism ofandrogens in vivo. Although CYP2C8 participates in themetabolism of several endogenous compounds, no car-diovascular or other potentially CYP2C8-related adverseeffects were observed in the Helsinki Heart Study, inwhich over 2000 middle-aged men with primary dyslipi-demia ingested the strong CYP2C8 inhibitor gemfibrozil600 mg twice daily for several years (Frick et al., 1987).
Furthermore, some natural compounds have beenreported to undergo metabolism by CYP2C8 in vitro(Table 3). CYP2C8 and CYP3A4 are the primaryenzymes involved in the in vitro metabolism of1-hydroxyl-2,3,5-trimethoxyxanthone, a constituent ofthe Tibetan medicinal plant Halenia elliptica (Fenget al., 2014). CYP2C8 is responsible for the mainmetabolic pathway of silybin, the active component ofsilymarin in vitro (Jancova et al., 2007). The CYP2C8inhibitor quercetin inhibited silybin O-demethylationby 80% in HLM, and recombinant CYP2C8 was themajor enzyme formingO-demethyl silybin, with a smallcontribution by CYP3A4. Furthermore, CYP2C8 is themajor enzyme responsible for the in vitro metabolism oftanshinol borneol ester, a combination of the naturalcompounds danshensu and borneol (Liu et al., 2010a).Recombinant CYP2C8 generated all five tanshinolborneol metabolites (M1-M5) observed in HLM incuba-tions, whereas recombinant CYP3A4 only produced theM4 metabolite.
IV. Pharmacogenetics
Nearly 100 nonsynonymous single nucleotide varia-tions (SNV) and short deletions, as well as essentialsplice site variants have been found in the CYP2C8gene. The variants described in the literature, dbSNPdatabase, or the 1000 Genomes project database arelisted in Table 5, together with their continentalfrequencies and predicted or experimentally deter-mined effects on protein function. The vast majority ofthe nonsynonymous variants are rare and occur atminor allele frequencies of 0.01 or less in all investi-gated populations.
A. Population Genetics
Three alleles, known as CYP2C8*2, *3, and *4,account for the majority of nonsynonymous variabilityof CYP2C8 in humans. Their frequencies differ signif-icantly both between and within continental popula-tions (Table 5, Fig. 6).
The CYP2C8*2 allele (c.805A.T, p.Cys266Phe) oc-curs mostly in individuals with a sub-Saharan African
Role of CYP2C8 in Drug Metabolism and Interactions 187
TABLE
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etal.,20
09;Adz
hube
iet
al.,20
10;McL
aren
etal.,20
10).*-allele
nom
enclature
was
retrieve
dfrom
theHuman
Cytochr
omeP45
0(C
YP)AlleleNom
enclatur
eDatab
ase(w
ww.cyp
alleles.ki.se).
*-allele
dbSNPID
Location
Nucleo
tide
Chan
geAminoAcidChan
ge
Enzy
meActivity
VariantAlleleFrequ
ency
InSilicoPrediction
African
Europe
anSou
thAsian
Eas
tAsian
American
SIF
TPolyP
hen
InVivo
InVitro
rs14
2470
035
Exo
n1
c.1A
.G
p.Met1?
0.00
450
00
0de
leteriou
spr
obab
lyda
mag
ing
rs37
3001
219
Exo
n1
c.7C
.A
p.Pro3T
hr
——
——
—tolerated
benign
rs53
0027
098
Exo
n1
c.40
A.T
p.Met14
Leu
00
0.00
10
0tolerated
benign
rs20
2131
138
Exo
n1
c.63
A.T
p.Arg21
Ser
——
——
—de
leteriou
sbe
nign
rs26
7602
643
Exo
n1
c.77
G.A
p.Arg26
Lys
——
——
—tolerated
benign
rs37
5170
154
Exo
n1
c.14
9T.C
p.Ile5
0Thr
——
——
—tolerated
benign
rs11
3939
225
Exo
n1
c.16
7A.G
p.Asn
56Ser
——
——
—tolerated
benign
↔rs37
6132
046
Exo
n2
c.19
9G.A
p.Val67
Met
——
——
—de
leteriou
spo
ssibly
damag
ing
rs17
8517
96Exo
n2
c.24
4G.A
p.Ala82
Thr
00
00.00
10
deleteriou
sbe
nign
rs17
8517
96Exo
n2
c.24
4G.T
p.Ala82
Ser
00
00.00
10
deleteriou
sbe
nign
rs20
1449
274
Exo
n2
c.26
3T.C
p.Ile8
8Thr
00
00
0.00
14de
leteriou
sbe
nign
rs37
2299
895
Exo
n2
c.26
8A.G
p.Asn
90Asp
——
——
—tolerated
benign
rs57
8254
206
Exo
n2
c.29
3G.T
p.Gly98
Val
00
0.00
10
0de
leteriou
spr
obab
lyda
mag
ing
rs19
9931
273
Intron
2c.33
1+2T
.C
——
——
——
—
rs36
9552
457
Exo
n3
c.34
5C.A
p.Ser11
5Arg
——
——
—de
leteriou
spr
obab
lyda
mag
ing
rs20
1739
495
Exo
n3
c.36
8T.A
p.Ile1
23Asn
——
——
—de
leteriou
spo
ssibly
damag
ing
rs37
7386
087
Exo
n3
c.37
0C.T
p.Arg12
4Trp
——
——
—de
leteriou
spr
obab
lyda
mag
ing
rs36
9591
911
Exo
n3
c.37
1G.A
p.Arg12
4Gln
——
——
—de
leteriou
spr
obab
lyda
mag
ing
rs18
8111
115
Exo
n3
c.37
3C.T
p.Arg12
5Cys
0.00
080
00
0de
leteriou
spo
ssibly
damag
ing
rs13
9650
638
Exo
n3
c.38
9C.A
p.Thr
130A
sn0
00.00
10
0de
leteriou
spo
ssibly
damag
ing
rs13
9650
638
Exo
n3
c.38
9C.T
p.Thr
130Ile
00
0.00
10
0tolerated
prob
ably
damag
ing
*3rs11
5720
80Exo
n3
c.41
6G.A
p.Arg13
9Lys
0.00
830.11
830.02
970.00
10.09
94tolerated
benign
↑↓↑
rs54
0288
649
Exo
n3
c.43
0C.G
p.Arg14
4Gly
00
0.01
020
0de
leteriou
spr
obab
lyda
mag
ing
rs20
0057
634
Exo
n3
c.44
9A.G
p.His15
0Arg
——
——
—tolerated
benign
rs20
1561
213
Exo
n3
c.47
2A.G
p.Lys15
8Glu
——
——
—de
leteriou
sbe
nign
*5rs72
5581
96Exo
n3
c.47
5delA
p.Thr
159P
rofsTer19
——
——
——
—non
ers57
6554
998
Exo
n4
c.49
7C.T
p.Pro16
6Leu
——
——
—de
leteriou
spr
obab
lyda
mag
ing
*6rs14
2886
225
Exo
n4
c.51
1G.A
p.Gly17
1Ser
00
00.00
60
tolerated
benign
↔rs55
3407
481
Exo
n4
c.51
6T.A
p.Cys17
2Ter
——
——
——
—rs14
1350
682
Exo
n4
c.52
5C.A
p.Cys17
5Ter
——
——
——
—
rs11
3008
582
Exo
n4
c.52
6A.G
p.Asn
176A
sp—
——
——
deleteriou
spr
obab
lyda
mag
ing
rs20
1219
972
Exo
n4
c.53
6G.C
p.Cys17
9Ser
——
——
—tolerated
possibly
damag
ing
rs41
2868
86Exo
n4
c.54
1G.A
p.Val18
1Ile
00.01
090
00.00
29tolerated
benign
rs14
7150
224
Exo
n4
c.54
4G.A
p.Val18
2Ile
——
——
—tolerated
benign
*7rs72
5581
95Exo
n4
c.55
6C.T
p.Arg18
6Ter
——
——
——
—non
e*8
rs54
3793
530
Exo
n4
c.55
7G.A
p.Arg18
6Gln
00
0.00
10
0de
leteriou
spr
obab
lyda
mag
ing
↓rs20
1899
315
Exo
n4
c.58
1T.A
p.Phe1
94Tyr
——
——
—de
leteriou
sbe
nign
rs20
1045
618
Exo
n4
c.60
2T.A
p.Phe
201T
yr0
00
0.00
10
deleteriou
spo
ssibly
damag
ing
rs14
6962
089
Exo
n4
c.63
5G.A
p.Trp
212T
er0.00
230
00
0—
—rs14
8974
310
Exo
n5
c.64
3G.A
p.Val21
5Ile
——
——
—tolerated
benign
*13
N.A.
Exo
n5
c.66
9T.G
p.Ile2
23Met
——
——
—tolerated
benign
↔rs56
9886
323
Exo
n5
c.70
3A.G
p.Lys23
5Glu
00
00.00
10
tolerated
benign
*14
rs18
8934
928
Exo
n5
c.71
2G.C
p.Ala23
8Pro
00
00.00
10
tolerated
benign
↓rs53
7006
401
Exo
n5
c.71
3C.T
p.Ala23
8Val
——
——
—tolerated
benign
rs20
0358
471
Exo
n5
c.71
6T.C
p.Leu
239P
ro—
——
——
tolerated
benign
rs53
6085
663
Exo
n5
c.72
1C.T
p.Arg24
1Ter
0.00
080
00
0—
—
rs11
5721
02Exo
n5
c.73
0A.G
p.Ile2
44Val
0.00
680
00
0tolerated
benign
*9N.A.
Exo
n5
c.74
0A.G
p.Lys24
7Arg
——
——
—tolerated
benign
↔
(con
tinued
)
188 Backman et al.
TABLE
5.—
Con
tinued
*-allele
dbSNPID
Location
Nucleo
tide
Chan
geAminoAcidChan
ge
Enzy
meActivity
VariantAlleleFrequ
ency
InSilicoPrediction
African
Europe
anSou
thAsian
Eas
tAsian
American
SIF
TPolyP
hen
InVivo
InVitro
rs14
1120
323
Exo
n5
c.76
7A.G
p.Asp
256G
ly—
——
——
deleteriou
spr
obab
lyda
mag
ing
rs52
7793
637
Exo
n5
c.78
1C.T
p.Arg26
1Trp
00
0.00
10
0de
leteriou
sbe
nign
rs37
0459
834
Exo
n5
c.78
2G.T
p.Arg26
1Leu
——
——
—de
leteriou
sbe
nign
*4rs10
5893
0Exo
n5
c.79
2C.G
p.Ile2
64Met
0.00
380.05
770.00
720
0.01
87de
leteriou
spr
obab
lyda
mag
ing
↓↑rs55
1515
028
Exo
n5
c.79
3G.A
p.Asp
265A
sn0.00
080
00
0de
leteriou
spr
obab
lyda
mag
ing
rs37
7675
927
Exo
n5
c.79
7G.T
p.Cys26
6Phe
——
——
—de
leteriou
spr
obab
lyda
mag
ing
*2rs11
5721
03Exo
n5
c.80
5A.T
p.Ile2
69Phe
0.18
910.00
40.01
230
0.01
15de
leteriou
spr
obab
lyda
mag
ing
↓↔rs37
3613
215
Exo
n5
c.81
6G.C
p.Glu27
2Asp
——
——
—tolerated
benign
*11
rs78
6375
71Exo
n6
c.82
0G.T
p.Glu27
4Ter
00
00.00
30
——
non
ers14
0599
093
Exo
n6
c.82
1A.G
p.Glu27
4Gly
——
——
—de
leteriou
sbe
nign
rs37
0806
022
Exo
n6
c.84
8A.G
p.Asn
283S
er—
——
——
tolerated
benign
rs53
7326
361
Exo
n6
c.95
5G.A
p.Val31
9Ile
00
00
0.00
14tolerated
benign
rs14
6806
199
Exo
n7
c.99
2T.C
p.Ile3
31Thr
0.00
150
0.00
410
0de
leteriou
spr
obab
lyda
mag
ing
rs14
8442
781
Exo
n7
c.10
28G.T
p.Ser34
3Ile
——
——
—tolerated
benign
rs19
9691
080
Exo
n7
c.10
60G.A
p.Glu35
4Lys
——
——
—de
leteriou
spr
obab
lyda
mag
ing
rs37
3461
548
Exo
n7
c.10
63A.T
p.Ile3
55Phe
——
——
—de
leteriou
spr
obab
lyda
mag
ing
rs45
4387
99Exo
n7
c.10
81C.T
p.Leu
361P
he0
0.00
10
00
tolerated
possibly
damag
ing
rs77
1470
96Exo
n7
c.10
93G.A
p.Gly36
5Ser
0.00
980
00
0tolerated
benign
rs14
7133
669
Exo
n7
c.10
96G.A
p.Val36
6Met
0.00
080.00
10
00.00
14de
leteriou
sbe
nign
rs37
5271
607
Exo
n7
c.11
44C.T
p.Pro38
2Ser
——
——
—de
leteriou
spr
obab
lyda
mag
ing
*10
N.A.
Exo
n7
c.11
49G.T
p.Lys38
3Asn
——
——
—de
leteriou
spr
obab
lyda
mag
ing
↔rs14
3386
810
Exo
n8
c.11
50G.A
p.Gly38
4Ser
00.00
10.00
10
0de
leteriou
spo
ssibly
damag
ing
rs55
3009
747
Exo
n8
c.11
54C.T
p.Thr
385Ile
00
0.00
10
0de
leteriou
spr
obab
lyda
mag
ing
rs26
7602
641
Exo
n8
c.11
65G.A
p.Ala38
9Thr
——
——
—tolerated
benign
rs72
5581
94Exo
n8
c.11
69T.C
p.Leu
390S
er—
——
——
tolerated
benign
rs74
4541
69Exo
n8
c.11
71C.A
p.Leu
391M
et—
——
——
deleteriou
spr
obab
lyda
mag
ing
rs20
1421
851
Exo
n8
c.11
78C.G
p.Ser39
3Cys
00
00
0.00
14de
leteriou
spr
obab
lyda
mag
ing
rs19
0807
911
Exo
n8
c.11
80G.A
p.Val39
4Met
00
00.00
10
deleteriou
spr
obab
lyda
mag
ing
rs20
1301
235
Exo
n8
c.11
87A.C
p.His39
6Pro
——
——
—de
leteriou
spo
ssibly
damag
ing
rs18
6285
658
Exo
n8
c.11
89G.A
p.Asp
397A
sn0
00
0.00
20
deleteriou
spo
ssibly
damag
ing
rs11
3669
182
Exo
n8
c.11
93A.G
p.Asp
398G
ly—
——
——
tolerated
benign
*3rs10
5096
81Exo
n8
c.11
96A.G
p.Lys39
9Arg
0.00
830.11
830.02
970.00
10.09
94tolerated
benign
↑↓↑
rs18
1982
392
Exo
n8
c.11
98G.T
p.Glu40
0Ter
00
00.00
10
——
rs66
5011
15Exo
n8
c.12
10C.G
p.Pro40
4Ala
——
——
—de
leteriou
spo
ssibly
damag
ing
↓rs15
0733
212
Exo
n8
c.12
25C.T
p.Pro40
9Ser
——
——
—de
leteriou
spr
obab
lyda
mag
ing
rs37
4605
743
Exo
n8
c.12
46A.C
p.Asn
416H
is—
——
——
deleteriou
sbe
nign
rs14
1209
951
Exo
n8
c.12
50G.T
p.Gly41
7Val
0.00
150
00
0de
leteriou
spr
obab
lyda
mag
ing
rs55
2247
471
Exo
n8
c.12
52A.T
p.Asn
418T
yr0
00.00
10
0de
leteriou
spr
obab
lyda
mag
ing
rs37
1330
493
Exo
n8
c.12
73T.C
p.Phe
425L
eu0.00
080
00
0de
leteriou
spr
obab
lyda
mag
ing
rs14
8348
784
Exo
n8
c.12
76A.G
p.Met42
6Val
——
——
—tolerated
benign
↔rs37
2999
683
Exo
n9
c.13
13A.G
p.Glu43
8Gly
——
——
—de
leteriou
spr
obab
lyda
mag
ing
rs14
3038
562
Exo
n9
c.13
24C.T
p.Arg44
2Cys
——
——
—de
leteriou
spo
ssibly
damag
ing
rs13
8495
387
Exo
n9
c.13
25G.A
p.Arg44
2His
——
——
—de
leteriou
spo
ssibly
damag
ing
rs36
9600
584
Exo
n9
c.13
27A.C
p.Met44
3Leu
——
——
—de
leteriou
sbe
nign
*12
rs38
3269
4Exo
n9
c.13
82_1
384d
elTTG
p.Val46
1del
——
——
——
—rs61
7573
18Exo
n9
c.14
13de
lAp.Val47
2Leu
fsTer23
——
——
——
—↔
rs52
9725
725
Exo
n9
c.14
14G.A
p.Val47
2Ile
00
00
0.00
29tolerated
benign
rs37
6016
142
Exo
n9
c.14
41C.T
p.Pro48
1Ser
——
——
—de
leteriou
spr
obab
lyda
mag
ing
rs14
0481
138
Exo
n9
c.14
66C.T
p.Pro48
9Leu
——
——
—de
leteriou
spr
obab
lyda
mag
ing
↔,unch
ange
dactivity;↓
,redu
cedactivity;↑,
increa
sedactivity;N
.A.,no
tav
ailable;
SIF
T,sortingintolerantfrom
tolerant
Role of CYP2C8 in Drug Metabolism and Interactions 189
ancestry. In sub-Saharan African populations, its allelefrequency ranges from about 0.10 in a Fulani populationin Burkina Faso to 0.37 in a Mbuti pygmy population inCongo (Cavaco et al., 2005; Rower et al., 2005; Parikhet al., 2007; Kudzi et al., 2009; Speed et al., 2009;Paganotti et al., 2011, 2012; 1000 Genomes ProjectConsortium, 2012; Arnaldo et al., 2013; Marwa et al.,2014). In an African-American population in the NewYork area, the allele frequency of CYP2C8*2 was 0.10
(Martis et al., 2013). The allele is also relativelycommon in the mixed Brazilian population with afrequency of 0.06, New York area Hispanic populationwith a frequency of 0.02, and North and South Indianpopulations, with frequencies of 0.03 and 0.01, respec-tively (Suarez-Kurtz et al., 2012; Martis et al., 2013;Minhas et al., 2013; Arun Kumar et al., 2015). TheCYP2C8*2 allele is very rare or absent in East Asianand European populations, with the exception of an
Fig. 6. Global distribution of CYP2C8*2, CYP2C8*3, and CYP2C8*4 alleles. Color intensity indicates allele frequency. References are given in the text.
190 Backman et al.
allele frequency of 0.01 in a Portuguese Europeansample (Nakajima et al., 2003; Muthiah et al., 2005;Cavaco et al., 2006; Pechandova et al., 2012; Vargenset al., 2012; Martis et al., 2013; Wu et al., 2013).The CYP2C8*3 allele is a haplotype consisting of
two nonsynonymous variants (c.416G.A, p.Arg139Lysand c.1196A.G, p.Lys399Arg), which appear to be ina complete or nearly complete linkage disequilibriumin all investigated populations (1000 Genomes ProjectConsortium, 2012). The linkage disequilibrium extendsalso beyond the CYP2C8 gene, as evidenced by a strongcorrelation between the CYP2C8*3 and CYP2C9*2(rs1799853; c.430C.T, p.Arg144Cys) alleles in theSwedish population (Yasar et al., 2002). The highestallele frequencies of CYP2C8*3 are seen in individualswith a European ancestry. In European populations,the allele frequency of CYP2C8*3 ranges from 0.069 inFaroe Islanders to 0.198 in a Portuguese population,with an apparent north-to-south cline from lower tohigher frequencies (Fig. 6; Yasar et al., 2002; Hallinget al., 2005; Cavaco et al., 2006; Speed et al., 2009; 1000Genomes Project Consortium, 2012; Pechandova et al.,2012; Suarez-Kurtz et al., 2012). The allele is also quitecommon in European American and North AmericanHispanic populations, with frequencies of 0.09 and 0.08,respectively (Martis et al., 2013). In themixed Brazilianand Ecuadorian populations, its frequency is 0.08 and0.07, and in a Chilean mestizo population it is 0.06(Roco et al., 2012; Suarez-Kurtz et al., 2012; Vicenteet al., 2014). There is wide variability in the frequencyof CYP2C8*3 in sub-Saharan African populations, evenwithin a country (Cavaco et al., 2005; Rower et al., 2005;Parikh et al., 2007; Kudzi et al., 2009; Arnaldo et al.,2013; Staehli Hodel et al., 2013; Marwa et al., 2014;Paganotti et al., 2014). For example, the frequency ofCYP2C8*3was found to be 0.00 in individuals in centralTanzania and as high as 0.10 in the Mwanza region ofTanzania (Staehli Hodel et al., 2013; Marwa et al.,2014).The CYP2C8*4 (c.792C.G, p.Ile264Met) allele has
its highest frequencies in European populations, withthe allele frequency ranging from 0.04 in a Spanishpopulation to 0.07 in the Irish (Cavaco et al., 2006;Speed et al., 2009; 1000 Genomes Project Consortium,2012; Pechandova et al., 2012). Its frequency was 0.03in a European American population and a mixed Bra-zilian population (Suarez-Kurtz et al., 2012; Martiset al., 2013). In Peruvian, Colombian, Puerto Rican, andNorth American Hispanic populations, the frequencyranges from 0.01 to 0.02 (1000 Genomes Project Con-sortium, 2012;Martis et al., 2013). TheCYP2C8*4 alleleis found with a frequency of about 0.03–0.04 in Indianindividuals and 0.01 in the Pakistani (1000 GenomesProject Consortium, 2012; Minhas et al., 2013). In EastAsian populations, the frequency of CYP2C8*4 isgenerally 0.01 or less, but a frequency of 0.02 was seenin anUighur Chinese population (Nakajima et al., 2003;
Muthiah et al., 2005; Speed et al., 2009; 1000 GenomesProject Consortium, 2012; Staehli Hodel et al., 2013;Wu et al., 2013). The allele is rare in individuals witha sub-Saharan African ancestry, with a frequency ofbelow 0.01 in all investigated sub-Saharan Africanpopulations and 0.01 in anAfricanAmerican population(Cavaco et al., 2005; Rower et al., 2005; Kudzi et al.,2009; 1000 Genomes Project Consortium, 2012; Arnaldoet al., 2013; Martis et al., 2013).
In addition to the common variants, rare nonsynon-ymous CYP2C8 variants exist in all continental pop-ulations (Table 5). A number of the rare CYP2C8variants can be predicted to result in a loss-of-functionbecause of premature termination of protein syn-thesis. The c.635G.A (p.Trp212Ter) and c.721C.T(p.Arg241Ter) variants have a combined allele frequencyof 0.003 in sub-Saharan African populations, and thec.820G.T (p.Glu274Ter) and c.1198G.T (p.Glu400Ter)variants have a combined allele frequency of 0.004 inEast Asians (1000 Genomes Project Consortium, 2012).Other predicted loss-of-function CYP2C8 variants werenot found in the 1000 Genomes Project populations,and data are too scarce to estimate their populationfrequencies.
B. Functional Studies
The functional effects of CYP2C8 variants have beeninvestigated using recombinantly expressed variantproteins and HLM with different CYP2C8 genotypes.Recombinant CYP2C8.2 has been quite consistentlyassociated with an about 50% decrease in the intrinsicclearance for paclitaxel 6a-hydroxylation, comparedwith CYP2C8.1 (Dai et al., 2001; Gao et al., 2010;Yu et al., 2013b). In addition, the intrinsic clearanceof amodiaquine has been reduced by 80–90% inCYP2C8.2 and that of repaglinide by 20% comparedwith CYP2C8.1 (Parikh et al., 2007; Yu et al., 2013b).Similarly, the intrinsic clearances of arachidonic acidand tanshinol borneol ester appeared to be lower byCYP2C8.2 than by CYP2C8.1, but the differences werenot statistically significant (Dai et al., 2001; Liu et al.,2010a). On the other hand, the intrinsic clearances forcerivastatin M-23 and M-1 metabolite formation and R-and S-ibuprofen hydroxylations have been nonsignificantlyhigher in CYP2C8.2 than in CYP2C8.1 (Kaspera et al.,2010; Yu et al., 2013b). Both the SIFT or Polyphen in silicopredictionalgorithms suggest that the aminoacid change inCYP2C8.2 is deleterious for CYP2C8 activity (Table 5).
In several studies, the intrinsic clearance for pacli-taxel 6a-hydroxylation by recombinant CYP2C8.3 hasbeen between 30 and 85% lower than by CYP2C8.1 (Daiet al., 2001; Soyama et al., 2001; Gao et al., 2010; Yuet al., 2013b). Other studies employing recombinantCYP2C8.3 have shown increased intrinsic clearancefor repaglinide and cerivastatin but reduced intrinsicclearance for R- and S-ibuprofen and nearly abolishedintrinsic clearance for amodiaquine (Kaspera et al.,
Role of CYP2C8 in Drug Metabolism and Interactions 191
2010; Parikh et al., 2007; Yu et al., 2013b). The intrinsicclearances of arachidonic acid to 11,12- and 14,15-epoxyeicosatrienoic acid and tanshinol borneol esterhave also been significantly lower by CYP2C8.3 than byCYP2C8.1 (Dai et al., 2001; Liu et al., 2010a). However,in a recent study expressing CYP2C8.3 together withcytochrome P450 reductase and cytochrome b5, theintrinsic clearance for paclitaxel 6a-hydroxylation wasabout twofold higher, that for amodiaquine about two-fold higher, that for rosiglitazone about 2.5-fold higher,and that for cerivastatin about 4.5-fold higher comparedwith CYP2C8.1 (Kaspera et al., 2011). A strongerbinding affinity of ligands to CYP2C8.3 together with anincrease in heme spin change during binding of ligandsand redox partners were suggested to partly explainthe increased catalytic activity (Kaspera et al., 2011).In one study, HLM heterozygous for the CYP2C8*3allele showed lowered paclitaxel 6a-hydroxylase activ-ity and in another study no change in amodiaquineN-deethylation compared with microsomes homozy-gous for CYP2C8*1 (Bahadur et al., 2002; Kasperaet al., 2011). Studies employing HLM heterozygous orhomozygous for CYP2C8*3 have shown increased in-trinsic clearance of pioglitazone and imatinib (Muschleret al., 2009; Khan et al., 2015). In silico predictionssuggest that neither of the amino acid changes inCYP2C8.3 affect CYP2C8 activity (Table 5). Takentogether, in vitro evidence concerning the functionaleffects of CYP2C8*3 suggests some degree of asubstrate-specific effect but is discrepant for somesubstrates in that both decreased and increased activ-ities have been reported.In three studies, paclitaxel 6a-hydroxylation intrinsic
clearance was reduced by about 70% by recombinantCYP2C8.4 compared with CYP2C8.1 (Singh et al., 2008;Gao et al., 2010; Yu et al., 2013b). Similarly, the intrinsicclearances of repaglinide and R- and S-ibuprofen havebeen 20, 50, and 53% lower by CYP2C8.4 than byCYP2C8.1, respectively (Yu et al., 2013b). On the otherhand, the intrinsic clearances of cerivastatin to M-23 andM-1 were about 2- to 2.5-fold higher by CYP2C8.4 than byCYP2C8.1 (Kaspera et al., 2010). The intrinsic clearanceof tanshinol borneol ester was not significantly differentbetweenCYP2C8.4 andCYP2C8.1 (Liu et al., 2010a). Onestudy suggests that the amino acid change in CYP2C8.4disrupts heme binding and results in an inactive protein(Singh et al., 2008). HLM heterozygous for CYP2C8*4showed a nonsignificant tendency for lower paclitaxel6a-hydroxylase activity (Bahadur et al., 2002). In silicopredictions suggest that the amino acid change inCYP2C8.4 is deleterious for CYP2C8 activity (Table 5).In vitro studies employing recombinant CYP2C8
have shown reduced paclitaxel 6a-hydroxylase activityin association with the p.Arg186Gln, p.Ala238Pro (*14),and p.Pro404Ala variants but no change in activity dueto the p.Gly171Ser, p.Ile223Met (*13), p.Lys247Arg,and p.Lys383Asn variants (Soyama et al., 2001; Hichiya
et al., 2005; Hanioka et al., 2010). In one study, thep.Ala238Pro and p.Ile223Met variants were associatedwith reduced amiodarone metabolism (Hanioka et al.,2011). One study demonstrated lack of CYP2C8 proteinexpression in association with the p.Glu274Ter (*11)nonsense variant (Yeo et al., 2011).
C. Effects on Drug Metabolism in Humans
In contrast to previous in vitro studies suggestinga reduced CYP2C8 activity in association with theCYP2C8*3 allele (Dai et al., 2001; Bahadur et al.,2002), the first pharmacokinetic study in humansshowed that the CYP2C8*3 allele was associated withreduced plasma concentrations of repaglinide (Niemiet al., 2003c). In this and later studies, individuals withtheCYP2C8*1/*3 genotype have had an approximately40–50% lower AUC of a subtherapeutic dose of repagli-nide than individuals with the CYP2C8*1/*1 genotype(Niemi et al., 2005b,c). However, this finding has notbeen fully replicated in studies with higher repaglinidedoses (Bidstrup et al., 2006; Tomalik-Scharte et al.,2011), suggesting that the effect of CYP2C8*3 allele onrepaglinide pharmacokinetics may be dose dependent.
Similarly to repaglinide, the CYP2C8*3 allele hasbeen associated with apparently increased clearance ofthe thiazolidinediones rosiglitazone and pioglitazone(Kirchheiner et al., 2006; Aquilante et al., 2008, 2013a;Tornio et al., 2008b). The AUCs of rosiglitazone or pioglit-azonehavebeenabout20–40% lower inCYP2C8*3 carriersthan in noncarriers, with an apparent gene-dose effect(Kirchheiner et al., 2006; Aquilante et al., 2008, 2013a;Tornio et al., 2008b). Furthermore, in a study in patientswith type 2 diabetes mellitus, the CYP2C8*3 allele hasbeen associated with significantly lower trough rosigli-tazone concentrations and an impaired lowering ofglycosylated hemoglobin (HbA1c) during rosiglitazonetreatment (Stage et al., 2013). In one study in AfricanAmerican subjects, the CYP2C8*2 allele had no impacton parent pioglitazone pharmacokinetics but was asso-ciated with impaired metabolism of pioglitazone to itsM3 metabolite (Aquilante et al., 2013c).
Although CYP2C8*2 has been associated with signif-icantly impaired amodiaquine metabolism in vitro(Parikh et al., 2007), the allele has not been clearlyassociated with amodiaquine efficacy or toxicity (Adjeiet al., 2008).However,more recent evidence suggests thatCYP2C8 genetic variability can influence the occurrenceof amodiaquine or chloroquine resistance in malariaparasites (Paganotti et al., 2011; Cavaco et al., 2013).
Studies in cancer patients have suggested that theCYP2C8*3 allele can slightly impair the clearance ofpaclitaxel (Henningsson et al., 2005; Bergmann et al.,2011). Some studies have also suggested that theCYP2C8*3 allele or other CYP2C8 variants may be riskfactors for paclitaxel-induced neurotoxicity or myelo-suppression and affect the benefit-to-risk ratio ofpaclitaxel therapy (Green et al., 2011; Leskelä et al.,
192 Backman et al.
2011; Hertz et al., 2012; Hertz et al., 2014; Lee et al.,2015). Further studies are required to clarify the roleof CYP2C8 genetic variants in affecting paclitaxelresponse.Some studies have reported significantly increased
plasma concentrations and apparently reduced clear-ance of racemic ibuprofen and its enantiomers inassociation with the CYP2C8*3 allele (Garcia-Martinet al., 2004; Martinez et al., 2005; Kara�zniewicz-Ładaet al., 2009). On the other hand, one study reportedenhanced clearance of R-ibuprofen in association withCYP2C8*3 (Lopez-Rodriguez et al., 2008). Becauseibuprofen is a substrate of CYP2C9, it is likely thatthe discrepancies are due to the strong linkage disequi-librium between CYP2C8*3 and CYP2C9*2 and re-duced ibuprofen clearance in CYP2C8*3 carriers is infact due to the CYP2C9*2 allele.Although CYP2C8 is not known to be involved in
bisphosphonate pharmacokinetics, an intronic SNV inCYP2C8 (rs1934951) has been associated with zole-dronic acid-induced osteonecrosis of the jaw in patientstreated for multiple myeloma (Sarasquete et al., 2008).In a more recent study, this SNV was associated withthe mandibular localization of bisphosphonate-inducedosteonecrosis (Balla et al., 2012). However, there was nosignificant relationship between the variant and thedevelopment of bisphosphonate-induced osteonecrosisof the jaw in men with prostate cancer (English et al.,2010) or in patients with multiple myeloma (Such et al.,2011). A meta-analysis found no significantly increasedsusceptibility to bisphosphonate-induced osteonecrosisof the jaw in rs1934951 carriers when all cancer typeswere pooled, but suggested a significant association inmultiple myeloma patients (Zhong et al., 2013).
V. In Vitro Inhibition and Induction ofCytochrome P450 2C8
A. Reversible Inhibition
1. Drugs That Act as Inhibitors of Cytochrome P4502C8. Several drugs, drug metabolites, and other com-pounds have been found to inhibit CYP2C8 activityreversibly in vitro (Tables 6 and 7). In an in vitroscreening of 209 commonly used drugs, 48 compoundsexhibited greater than 50% inhibition of recombinantCYP2C8 activity at an inhibitor concentration of 30 mM(Walsky et al., 2005a). Montelukast, candesartan cilex-etil, zafirlukast, clotrimazole, felodipine, and mometa-sone furoate inhibited CYP2C8 with concentrationssupporting half of the maximal inhibition (IC50) of#3 mM in recombinant CYP2C8 and HLM. In anotherstudy, the inhibition of CYP2C8 by montelukast wasfound to be competitive and selective, with reversibleinhibition constants (Ki) ranging from 0.0092 to 0.15 mM,depending on the protein concentration used in theincubation (Walsky et al., 2005b). However, despitetheir strong inhibitory effect on CYP2C8 in vitro,
neither montelukast nor zafirlukast affected the phar-macokinetics of CYP2C8 substrate drugs in vivo(Jaakkola et al., 2006b; Kajosaari et al., 2006b; Kimet al., 2007). The lack of in vivo effect is likely explainedby their extensive plasma protein binding (.99%)(FDA, 1998; Dekhuijzen and Koopmans, 2002). Alsothe inhibition of CYP2C8 by candesartran cilexetil(prodrug of candesartan), clotrimazole, and mometa-sone furoate are probably not clinically relevant. Theantifungal clotrimazole and anti-inflammatory mome-tasone furoate are topically applied and are thereforeunlikely to cause interactions because of low systemicconcentrations (Walsky et al., 2005a). In the systemiccirculation, candesartan cilexetil is cleaved to candesartan,and, consequently, the likelihood of a drug interactionelicited by its prodrug is low. Furthermore, predictionssuggested a relatively weak potential for drug-druginteractions due to CYP2C8 inhibition by felodipine. Nodrug interaction studies between felodipine andCYP2C8 substrates have been reported.
Trimethoprim, an antimicrobial agent, is a competi-tive inhibitor of CYP2C8 in vitro (Wen et al., 2002), witha Ki value typically around 10–30 mM in HLM (Table 6).The inhibition of CYP2C8 by trimethoprim seems to berather selective, because it does not inhibit CYP1A2,CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 atconcentrations below 100 mM. In healthy subjects, tri-methoprim has moderately increased the plasma expo-sure to several CYP2C8 substrate drugs (section VI.).
The flavonoid quercetin is one of the earliest in vitroinhibitors of CYP2C8 detected. In studies of paclitaxelmetabolism, it was observed that quercetin, unlikeCYP3A4 inhibitors, inhibited paclitaxel 6a-hydroxylation(Harris et al., 1994; Kumar et al., 1994). Because itwas shown that the 6a-hydroxylation of paclitaxel ismediated by CYP2C8, it was evident that quercetin isan inhibitor of this enzyme (Rahman et al., 1994).Quercetin inhibits CYP2C8 competitively with a Ki of0.03–20 mM (Table 7) and is classified as a "preferred"probe in vitro inhibitor of CYP2C8 by the FDA (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm). However, quercetin is not selectivefor CYP2C8; it also inhibits CYP1A2, CYP2C9,CYP2C19, CYP2D6, and CYP3A4 with IC50 values of3.1–47 mM (Obach, 2000; Zou et al., 2002). In vivo,quercetin at steady state did not affect the pharmaco-kinetics of rosiglitazone (Kim et al., 2005a).
The lipid-lowering drug gemfibrozil is a moderate,direct competitive inhibitor of CYP2C8 in vitro (Wenet al., 2001; Prueksaritanont et al., 2002; Wang et al.,2002), with a Ki range between 9.3 and 270 mM(Table 6). Gemfibrozil also inhibits CYP2C9 andCYP2C19 with Ki values of 5.8 and 24 mM, respectively,and CYP1A2 with a Ki of 82 mM (Wen et al., 2001).Moreover, it inhibits several drug transporters in vitro,most notably OATP1B1 (lowest reported Ki = 4 mM)
Role of CYP2C8 in Drug Metabolism and Interactions 193
TABLE
6Dru
gs,dr
ugmetab
olites,an
dsomeothe
rcompo
unds
that
actas
reve
rsible
CYP2C
8inhibitors
Inhibitor
Therap
euticUse
and/or
Dru
gClass
IC50
Ki
Mod
eof
Inhibition
Test
System
Marke
rRea
ctiona
I maxb
f ub
I/Kic
I u/K
icReferen
ces
mM
(mg/
ml)
mM
(mg/
ml)
mM
2-Oxo
-clopido
grel
Dru
gmetab
olite
33.9
rCYP2C
8DBF
Hag
iharaet
al.,20
084.1
rCYP2C
8Ceri-1
Floyd
etal.,20
124.2
rCYP2C
8Ceri-23
Floyd
etal.,20
1232
.0HLM
Amo
Tornio
etal.,20
142,4-Dichloroa
niline
Dru
gmetab
olite
99.4
HLM
Rosi-OH
Wuet
al.,20
144-Hyd
roxy
ospe
mifen
eDru
gmetab
olite
27.7
HLM
Amo
FDA,20
13i;Turp
einen
etal.,20
134’-H
ydroxy
ospe
mifen
eDru
gmetab
olite
7HLM
Amo
FDA,20
13i;Turp
einen
etal.,20
137-Epi-paclitaxe
lPaclitaxe
lep
imer
2.1
HLM
Pacli
Zhan
get
al.,20
09b
7-O-succinyl
macrolactin
AAntibiotic
20.5
HLM
Rosi-OH
Bae
etal.,20
1417
b-E
stradiol
(estradiol)
Hormon
alreplacem
ent
therap
y21
.5rC
YP2C
8Amo
Walsk
yet
al.,20
05a
6.6
Com
petitive
HLM
Amo
Van
denB
rink
etal.,20
1123
.8Com
petitive
HLM
Mon
teVan
denB
rink
etal.,20
1117
.7Com
petitive
HLM
Pacli
Van
denB
rink
etal.,20
118.9
Com
petitive
HLM
Rep
aVan
denB
rink
etal.,20
1123
.8Com
petitive
HLM
Rosi
Van
denB
rink
etal.,20
1119
HLM
Amo
Nirog
iet
al.,20
14Abiraterone
Anticancer,
CYP17
A1
inhibitor
1.6
HLM
n/a
0.65
0.00
20.81
,0.01
EMA,20
12a
Abirateroneacetate
Antican
cer,
CYP17
A1
inhibitor
1.3
HLM
n/a
EMA,20
12a
Acotiam
ide(Z-338
)Antidyspe
ptic,
acetylch
olinesterase
inhibitor
121
Com
petitive
HLM
DBF
Fur
utaet
al.,20
04,
Afatinib
Anticanc
er,PKI
94.83
HLM
Pacli
0.07
80.42
8,0.01
,0.01
Wan
get
al.,20
14a
Alisertib
(MLN82
37)
Antican
cer,
PKI
16.3
n/a
n/a
Pus
alka
ret
al.,20
14Alitretinoin(9-cis-retinoic
acid)
Anticanc
er,retinoid
17.6
20.2
HLM
Taz
a0.28
0.01
Attar
etal.,20
03
Amlodipine
Antihyp
ertens
ive,
CCB
10.7
rCYP2C
8Amo
0.03
190.07
,0.01
,0.01
Walsk
yet
al.,20
05a
6.4
rCYP2C
8Ceri-1
0.01
,0.01
Floyd
etal.,20
124.0
rCYP2C
8Ceri-23
0.02
,0.01
Floyd
etal.,20
129.4
HLM
Amo
,0.01
,0.01
Nirog
iet
al.,20
14Amod
iaqu
ine
Antimalarial
11.7
HLM
Mon
te0.04
7,0.01
Van
denB
rink
etal.,20
11.10
0HLM
Pacli
,0.01
Van
denB
rink
etal.,20
111.9
HLM
Rep
a0.02
Van
denBrinket
al.,20
1111
.0HLM
Rosi
,0.01
Van
denB
rink
etal.,20
11Anas
trozole
Anticanc
er,arom
atas
einhibitor
4810
Com
petitive
HLM
Tolbu
0.16
0.60
0.02
0.01
Grimm
andDyroff,19
97
Anidulafungin
Antifunga
l12
HLM
Amo
3.07
0.16
0.51
0.08
Dam
leet
al.,20
09Apo
morph
ine
Anti-Parkinson,do
pamine
agon
ist
1–10
rCYP2C
8DBF
4,0.01
8.00
,0.08
Salminen
etal.,20
11
Apr
emilas
tAntips
oriatic,
PDE4inhibitor
56.1
HLM
Pacli
0.76
40.32
0.03
,0.01
FDA,20
14e
Ataza
navir
Antiviral,pr
otea
seinhibitor
2.1
n/a
n/a
7.66
0.14
3.65
0.51
FDA,20
15b
Atorvas
tatin(acid,
parent)
Antihyp
erlipide
mic,
HMG-C
oAredu
ctas
einhibitor
38.4
15.9
Mixed
HLM
Pacli
0.09
80.02
,0.01
,0.01
Tornioet
al.,20
05
38.4
HLM
Pacli
,0.01
,0.01
Sak
aeda
etal.,20
0621
.9HLM
Amo
,0.01
,0.01
Jenk
inset
al.,20
1155
.7rC
YP2C
8Fluo
,0.01
,0.01
Sch
elleman
etal.,20
14Atorvas
tatinacyl-b- D
glucu
ronide(G
2)Dru
gmetab
olite
45HLM
Amo
Jenkinset
al.,20
11
(con
tinued
)
194 Backman et al.
TABLE
6—Con
tinued
Inhibitor
Therap
euticUse
and/or
Dru
gClass
IC50
Ki
Mod
eof
Inhibition
Test
System
Marke
rRea
ctiona
I maxb
f ub
I/Kic
I u/K
icReferen
ces
Atorvas
tatinlacton
eAntihyp
erlipide
mic,HMG-
CoA
redu
ctas
einhibitor
28.8
HLM
Pacli
Sak
aeda
etal.,20
06
Atraz
ine
Pesticide
31.3
HLM
Amo
Aba
sset
al.,20
09Axitinib
Antican
cer,
PKI
0.5
HLM
Pacli
0.16
0.01
0.32
,0.01
FDA,20
12f
0.11
HLM
Amo
2.90
0.03
Filpp
ula
etal.,20
140.17
HLM
Pacli
0.94
,0.01
Wan
get
al.,20
14a
AZD26
24Antips
ychotic,ne
urokinin-3
receptor
andtach
ykinin
receptor
3an
tago
nist
83.3
HLM
Amo
0.7
0.02
Liet
al.,20
10
Azilsartanmed
oxom
ilAntihyp
ertens
ive,
prod
rug
3.5
HLM
Pacli
FDA,20
11f
Belinostat
Anticanc
er,histone
deacetylas
einhibitor
100
HLM
n/a
100
0.07
12.00
0.14
FDA,20
14c
Belinostat3-ASBA
(M24
)Dru
gmetab
olite
49.1
HLM
n/a
FDA,20
14c
Belinostatacid
(M26
)Dru
gmetab
olite
22.1
HLM
n/a
FDA,20
14c
Belinostatam
ide
Dru
gmetab
olite
30.8
HLM
n/a
FDA,20
14c
BelinostatPX10
6507
Dru
gmetab
olite
13.8
HLM
n/a
FDA,20
14c
Ben
zbromaron
eAntihyp
eruricemic,XO
inhibitor
0.05
5Com
petitive
HLM
Amo
Van
denB
rink
etal.,20
11
0.38
Com
petitive
HLM
Mon
teVan
denB
rink
etal.,20
110.95
Com
petitive
HLM
Pacli
Van
denB
rink
etal.,20
110.15
Com
petitive
HLM
Rep
aVan
denB
rink
etal.,20
110.36
Com
petitive
HLM
Rosi
Van
denB
rink
etal.,20
11(2
)-N-3-ben
zyl-
phen
obarbital
Phe
noba
rbital
deriva
tive
34HLM
Pacli
Cai
etal.,20
04
Bezafibrate
Antihyp
erlipide
mic,PPARa
agon
ist
74HLM
Pacli
39.5
0.05
1.07
0.05
Fujinoet
al.,20
03a
9.7
Com
petitive
HLM
Pacli
4.07
0.20
Kajosaa
riet
al.,20
05a
Bisph
enol
ABisph
enol
97Non
compe
titive
rCYP2C
8Ami
Niw
aet
al.,20
00BTFM
gemfibrozil
Gem
fibrozilan
alog
13HLM
Amo
Jenk
inset
al.,20
11BTFM
gemfibrozilacyl-
b- D-glucu
ronide
Gem
fibrozilacyl-b-D-
gluc
uronide
analog
37HLM
Amo
Jenkinset
al.,20
11
Cab
ozan
tinib
Antican
cer,
PKI
5.0
rCYP2C
8n/a
3.27
,0.00
31.31
,0.01
FDA,20
12c
6.4
4.6
Non
compe
titive
HLM
Amo
0.71
,0.01
FDA,20
12c
3.8
4.6
Non
compe
titive
HLM
Amo
0.71
,0.01
Lacyet
al.,20
15;N
guye
net
al.,20
15Can
agliflozin
Antidiab
etic,SGLT2
inhibitor
75n/a
n/a
7.60
0.01
70.20
,0.01
FDA,20
13e
Can
agliflozin
glucu
ronide
(M7)
Dru
gmetab
olite
64n/a
Amo
FDA,20
13e
Can
desa
rtan
Antihyp
ertens
ive,
ARB
36.2
rCYP2C
8Amo
0.19
0.00
20.01
,0.01
Walsk
yet
al.,20
05a
Can
desa
rtan
cilexe
til
Antihyp
ertens
ive,
prod
rug
0.49
6rC
YP2C
8Amo
0.41
,0.01
1.65
0.02
Walsk
yet
al.,20
05a
3.04
HLM
Amo
0.27
,0.01
Walsk
yet
al.,20
05a
Carba
ryl
Pesticide
34.0
HLM
Amo
Aba
sset
al.,20
09Carve
dilol
Antihyp
ertens
ive
16.6
rCYP2C
8Amo
0.25
80.05
0.03
,0.01
Walsk
yet
al.,20
05a
Cefur
oxim
eax
etil
Antibiotic,pr
odru
g11
.1rC
YP2C
8Amo
19.6
0.67
3.53
2.37
Walsk
yet
al.,20
05a
Celecox
ibAnti-inflam
matory,
NSAID
15.9
rCYP2C
8Amo
1.85
0.03
0.23
,0.01
Walsk
yet
al.,20
05a
4.9
Com
petitive
HLM
Amo
0.38
0.01
Van
denB
rink
etal.,20
117.9
Com
petitive
HLM
Mon
te0.23
,0.01
Van
denB
rink
etal.,20
1154
.4Com
petitive
HLM
Pacli
0.03
,0.01
Van
denB
rink
etal.,20
113.1
Com
petitive
HLM
Rep
a0.60
0.02
Van
denB
rink
etal.,20
115.1
Com
petitive
HLM
Rosi
0.36
0.01
Van
denB
rink
etal.,20
119.9
rCYP2C
8Ceri-1
0.37
0.01
Floyd
etal.,20
125.4
rCYP2C
8Ceri-23
0.69
0.02
Floyd
etal.,20
12Ceritinib
Antican
cer,
PKI
0.6d
4.86
dHLM
Amo
1.81
0.02
80.37
0.01
FDA,20
14i
0.6d
HLM
Pacli
6.03
0.17
FDA,20
14i
(con
tinued
)
Role of CYP2C8 in Drug Metabolism and Interactions 195
TABLE
6—Con
tinued
Inhibitor
Therap
euticUse
and/or
Dru
gClass
IC50
Ki
Mod
eof
Inhibition
Test
System
Marke
rRea
ctiona
I maxb
f ub
I/Kic
I u/K
icReferen
ces
Cerivas
tatin(acid,
parent)
Antihyp
erlipide
mic,HMG-
CoA
redu
ctas
einhibitor
34.4
HLM
Pacli
0.00
85,0.01
,0.01
,0.01
Fujinoet
al.,20
04
30.0
31.7
Mixed
HLM
Pacli
,0.01
,0.01
Tornioet
al.,20
0529
.8HLM
Pacli
,0.01
,0.01
Sak
aeda
etal.,20
064.2
Com
petitive
HLM
Amo
,0.01
,0.01
Van
denB
rink
etal.,20
114.6
Com
petitive
HLM
Mon
te,0.01
,0.01
Van
denB
rink
etal.,20
1177
.4Com
petitive
HLM
Pacli
,0.01
,0.01
Van
denB
rink
etal.,20
114.4
Com
petitive
HLM
Rep
a,0.01
,0.01
Van
denB
rink
etal.,20
1113
.4Com
petitive
HLM
Rosi
,0.01
,0.01
Van
denB
rink
etal.,20
11Cerivas
tatinlacton
eAntihyp
erlipide
mic,HMG-
CoA
redu
ctas
einhibitor
44.3
HLM
Pacli
Sak
aeda
etal.,20
06
Chlorp
yrifos
Pesticide
22.2
HLM
Amo
Aba
sset
al.,20
09Chlorp
romaz
ine
Antipsych
otic
20HLM
Amo
0.47
00.05
0.05
,0.01
Nirog
iet
al.,20
14Cim
etidine
Antiulcerative,
H2R
A25
0HLM
Pacli
120.81
0.10
0.08
Mon
sarrat
etal.,19
97Ciprofibrate
Antihyp
erlipide
mic,PPARa
agon
ist
441
HLM
Pacli
83.0
0.01
0.38
,0.01
Fujinoet
al.,20
03a
Clofazimine
Antilepr
ic14
.1HLM
Pacli
Shimok
awaet
al.,20
15Clopido
grel
Antithrombo
tic,
platelet
aggreg
ationinhibitor
10.2
rCYP2C
8Amo
0.06
0.02
0.01
,0.01
Walsk
yet
al.,20
05a
33.2
rCYP2C
8DBF
,0.01
,0.01
Hag
iharaet
al.,20
082.8
rCYP2C
8Ceri-1
0.04
,0.01
Floyd
etal.,20
123.4
rCYP2C
8Ceri-23
0.04
,0.01
Floyd
etal.,20
1253
.6HLM
Amo
,0.01
,0.01
Tornioet
al.,20
14Clopido
grel
carbox
ylic
acid
Dru
gmetab
olite
.50
.0rC
YP2C
8DBF
Hag
iharaet
al.,20
0810
7rC
YP2C
8Ceri-1
Floyd
etal.,20
1213
6rC
YP2C
8Ceri-23
Floyd
etal.,20
12Clopido
grel
active
metab
olite
Dru
gmetab
olite
.50
.0rC
YP2C
8DBF
Hag
iharaet
al.,20
08
Clotrim
azole
Antifung
al2.5
Non
compe
titive
rCYP2C
8Torse
0.00
8,0.01
Onget
al.,20
000.72
5rC
YP2C
8Amo
0.02
Walsk
yet
al.,20
05a
0.77
6HLM
Amo
0.02
Walsk
yet
al.,20
05a
0.12
Com
petitive
HLM
Amo
0.07
Van
denB
rink
etal.,20
110.27
Com
petitive
HLM
Mon
te0.03
Van
denB
rink
etal.,20
110.22
Com
petitive
HLM
Pacli
0.04
Van
denB
rink
etal.,20
110.19
Com
petitive
HLM
Rep
a0.04
Van
denB
rink
etal.,20
111.9
Com
petitive
HLM
Rosi
,0.01
Van
denB
rink
etal.,20
110.80
3HLM
Pacli
0.02
Lee
etal.,20
12a
Cob
icistat
Antiviral,ph
armacok
inetic
inhibitor
30.1
HLM
Pacli
2.38
0.03
0.16
,0.01
FDA,20
12j
CP-778
875
Antihyp
erlipide
mic,PPARa
agon
ist
1.83
HLM
Amo
Kalgu
tkar
etal.,20
13
Cyclosp
orine
Immun
osupp
ressan
t,calcineu
rininhibitor
79rC
YP2C
8Pacli
1.11
0.07
0.03
,0.01
Yoshida
etal.,20
12
CYP3cide(PF-049
8151
7)Pharmacok
inetic
inhibitor
78HLM
Pacli
Walsk
yet
al.,20
12Dab
rafenib
Antican
cer,
PKI
7.7–
8.2
HLM
Rosi
2.85
0.00
30.74
,0.01
Law
renc
eet
al.,20
14Dalcetrap
ibAntihyp
erlipide
mic,
cholesterylester
tran
sfer
proteininhibitor
1.5
HLM
Pacli
9.70
12.93
Derks
etal.,20
09
Dan
azol
Hyp
oestroge
nic,
hype
rand
roge
nic,
ethisteron
ede
riva
tive
1.95
HLM
Pacli
0.21
0.22
Lee
etal.,20
12a
Das
abuvir(A
BT-333
)Antiviral,NSB5inhibitor
;17
Com
petitive
n/a
n/a
2.09
0.00
5;0.25
,0.01
FDA,20
14k
Das
atinib
Anticanc
er,PKI
123.6
HLM
Pacli
0.13
0.04
0.04
,0.01
FDA,20
06a
38.6
HLM
Pacli
,0.01
,0.01
Kim
etal.,20
13b
6.31
HLM
Pacli
0.02
,0.01
Wan
get
al.,20
14a
(con
tinued
)
196 Backman et al.
TABLE
6—Con
tinued
Inhibitor
Therap
euticUse
and/or
Dru
gClass
IC50
Ki
Mod
eof
Inhibition
Test
System
Marke
rRea
ctiona
I maxb
f ub
I/Kic
I u/K
icReferen
ces
N-deb
utyldroned
aron
e(SR35
021)
Dru
gmetab
olite
24.4
36.6
Non
compe
titive
HLM
Pacli
FDA,20
09a
N-deethyl
sunitinib
(SU12
662)
Dru
gmetab
olite
52HLM
Pacli
FDA,20
06b
N-dem
ethylim
atinib
Dru
gmetab
olite
99HLM
Pacli
FDA,20
0131
.312
.8Mixed
HLM
Amo
Filpp
ula
etal.,20
12N-dem
ethyltoremifen
eDru
gmetab
olite
2.1
HLM
Pacli
Kim
etal.,20
11b
Deferas
irox
Antido
te,iron
chelating
agen
t10
0HLM
Pacli
0.46
0.01
,0.01
,0.01
FDA,20
05a
Deferas
irox
metab
olite
CGP82
813A
Dru
gmetab
olite
160
HLM
Pacli
FDA,20
05a
Dex
amethas
one
Anti-inflam
matory,
glucu
corticoid
12.0
rCYP2C
8Amo
8.15
1.36
Walsk
yet
al.,20
05a
Diclofena
cAnti-inflammatory,
NSAID
54HLM
Amo
6.28
,0.00
50.23
,0.01
Jenk
inset
al.,20
11Diclofena
cacyl
gluc
uron
ide
Dru
gmetab
olite
14HLM
Amo
Jenk
inset
al.,20
11Diethyldithiocarbam
ate
Alcoh
olic
detergen
t12
9.5
rCYP2C
8Dia
Sai
etal.,20
0046
4.1
rCYP2C
8Phen
aSai
etal.,20
00Diethylstilbe
strol
Syn
thetic
estrog
en8.0
Com
petitive
HLM
Pacli
Quet
al.,20
11Diltiaz
emAntihyp
ertens
ive,
CCB
25rC
YP2C
8Ceri-1
0.33
50.22
0.03
,0.01
Floyd
etal.,20
1212
4rC
YP2C
8Ceri-23
,0.01
,0.01
Floyd
etal.,20
12Dox
orubicin
Anticanc
er2
HLM
Pacli
1.63
0.24
1.63
0.39
Mon
sarrat
etal.,19
9764
.8Com
petitive
HLM
Pacli
0.03
,0.01
Bun
etal.,20
0390
Non
compe
titive
HLM
Luc
i0.02
,0.01
Mas
eket
al.,20
11Dulox
etine
Antide
pressa
nt,SNRI
180
HLM
Pacli
0.07
90.05
,0.01
,0.01
FDA,20
08b
60HLM
Amo
,0.01
,0.01
Paris
etal.,20
09Efavirenz
Antiviral,NNRTI
4.0
rCYP2C
8Amo
12.6
0.00
56.30
0.03
Parikhet
al.,20
076.05
Com
petitive
rCYP2C
8Amo
2.08
0.01
Xuan
dDesta,20
134.78
Com
petitive
HLM
Amo
2.64
0.01
Xuan
dDesta,20
13Eltrombo
pag
Antihem
orrh
agic,c-mpl
receptor
agon
ist
24.8
HLM
Pacli
29,0.01
2.34
0.02
FDA,20
08c
Enz
alutam
ide
Antican
cer,
antian
drog
en10
5.5
Mixed
HLM
Amo
35.7
0.02
6.50
0.13
FDA,20
12k
Enza
lutamideM1
Dru
gmetab
olite
20HLM
Amo
FDA,20
12k
Enza
lutamideM2
Dru
gmetab
olite
28HLM
Amo
FDA,20
12k
Erlotinib
Anticancer,
PKI
6.17
5.8
Com
petitive
HLM
Pacli
6.06
0.10
1.05
0.10
Don
get
al.,20
119.5
HLM
Pacli
1.28
0.13
Kim
etal.,20
13b
4.02
HLM
Pacli
1.51
0.15
Wan
get
al.,20
14a
Esomep
razole
(S-
omep
razole)
Antiulcerative,
PPI
31.0
HLM
Amo
4.5
0.05
0.29
0.02
Zvy
agaet
al.,20
12
Ethionam
ide
Antitube
rculosis
110
HLM
Pacli
12.99
0.70
0.24
0.17
Shimok
awaet
al.,20
15Etrav
irine
Antiviral,NNRTI
19.6
Non
compe
titive
HLM
Pacli
2.2
0.01
0.11
,0.01
FDA,20
08a
Exe
mestane
Anticanc
er,arom
atas
einhibitor
13.5
rCYP2C
8Amo
0.06
00.10
,0.01
,0.01
Walsk
yet
al.,20
05a
Feb
uxo
stat
Antihyp
erur
icem
ic,XO
inhibitor
20n/a
n/a
16.78
0.00
70.84
,0.01
Naiket
al.,20
12
Felod
ipine
Antihyp
ertens
ive,
CCB
0.72
6rC
YP2C
8Amo
0.00
730.00
40.02
,0.01
Walsk
yet
al.,20
05a
1.20
HLM
Amo
0.01
,0.01
Walsk
yet
al.,20
05a
Fen
itrothion
Pesticide
4.3
HLM
Amo
Aba
sset
al.,20
09Fen
ofibrate
Antihyp
erlipide
mic,
PPARaag
onist
288
HLM
Pacli
23.83
,0.01
0.17
,0.01
Fujinoet
al.,20
03a
92.6
Com
petitive
HLM
Pacli
0.26
,0.01
Kajosaa
riet
al.,20
05a
2.39
rCYP2C
8Amo
19.94
0.20
Walsk
yet
al.,20
05a
4.8
rCYP2C
8Fluo
9.93
0.10
Sch
elleman
etal.,20
14Fluox
ymesterone
Andr
ogen
ic,3-ox
oand
rosten
(4)de
riva
tive
16rC
YP2C
8Ceri-1
Floyd
etal.,20
12
16rC
YP2C
8Ceri-23
Floyd
etal.,20
12 (con
tinued
)
Role of CYP2C8 in Drug Metabolism and Interactions 197
TABLE
6—Con
tinued
Inhibitor
Therap
euticUse
and/or
Dru
gClass
IC50
Ki
Mod
eof
Inhibition
Test
System
Marke
rRea
ctiona
I maxb
f ub
I/Kic
I u/K
icReferen
ces
Fluticasone
Anti-inflam
matory,
gluc
ocorticoid
0.58
HLM
Pacli
0.00
023
0.01
,0.01
,0.01
FDA,20
13c
FluticasoneM10
metab
olite
Dru
gmetab
olite
80HLM
Pacli
FDA,20
13c
Fluva
statin
(acid,
parent)
Antihyp
erlipide
mic,HMG-
CoA
redu
ctas
einhibitor
20HLM
Pacli
0.46
10.01
0.05
,0.01
Fisch
eret
al.,19
99
36.7
18.9
Mixed
HLM
Pacli
0.02
,0.01
Tornioet
al.,20
0515
.1rC
YP2C
8Amo
0.06
,0.01
Walsk
yet
al.,20
05a
70.2
HLM
Pacli
0.01
,0.01
Sak
aeda
etal.,20
06Fluva
statin
lacton
eAntihyp
erlipide
mic,HMG-
CoA
redu
ctas
einhibitor
55.4
HLM
Pacli
Sak
aeda
etal.,20
06
Gefitinib
Anticanc
er,PKI
31.0
HLM
Pacli
0.8
0.10
0.05
,0.01
Kim
etal.,20
13b
12.3
HLM
Amo
0.13
0.01
Filpp
ulaet
al.,20
148.69
HLM
Pacli
0.09
,0.01
Wan
get
al.,20
14a
Gem
fibrozil
Antihyp
erlipide
mic,PPARa
agon
ist
49Hep
Ceri-23
100
,0.03
4.08
0.12
Pru
eksa
ritano
ntet
al.,20
0287
Com
petitive
HLM
Pacli
1.15
0.03
Pru
eksa
ritano
ntet
al.,20
0278
rCYP2C
8Ceri-1
2.56
0.08
Wan
get
al.,20
0268
rCYP2C
8Ceri-23
2.94
0.09
Wan
get
al.,20
02.25
027
3Com
petitive
HLM
Ceri-1
,0.37
,0.01
Wan
get
al.,20
0295
69Com
petitive
HLM
Ceri-23
1.45
0.04
Wan
get
al.,20
0291
75–76
Com
petitive
HLM
Pacli
1.33
0.04
Wan
get
al.,20
0248
Mixed
HLM
Pacli
4.17
0.13
Fujinoet
al.,20
03a
55.4
Mixed
HLM
Pacli
1.81
0.05
Fujinoet
al.,20
03b
36.8
rCYP2C
8Ceri-1
5.44
0.16
Shitara
etal.,20
0429
.7rC
YP2C
8Ceri-23
6.73
0.20
Shitara
etal.,20
0411
969
.0Non
compe
titive
HLM
Rosi-OH
1.45
0.04
Hru
skaet
al.,20
0530
.4Com
petitive
HLM
Pacli
3.29
0.10
Kajosaa
riet
al.,20
05a
75.6
rCYP2C
8Amo
2.65
0.08
Walsk
yet
al.,20
05a
59HLM
Pio
3.39
0.10
Jaak
kola
etal.,20
06c
120
HLM
Pacli
1.67
0.05
Ogilvie
etal.,20
0610
7HLM
Mon
te1.87
0.06
Karon
enet
al.,20
1063
HLM
Mon
te-4
3.18
0.10
Karon
enet
al.,20
1012
0HLM
Amo
1.67
0.05
Jenkinset
al.,20
1110
.2Com
petitive
HLM
Amo
9.80
0.29
Van
denB
rink
etal.,20
1113
.5Com
petitive
HLM
Mon
te7.41
0.22
Van
denB
rink
etal.,20
11.10
0Com
petitive
HLM
Pacli
1.00
0.03
Van
denB
rink
etal.,20
119.3
Com
petitive
HLM
Rep
a10
.75
0.32
Van
denB
rink
etal.,20
1136
.1Com
petitive
HLM
Rosi
2.77
0.08
Van
denB
rink
etal.,20
1114
rCYP2C
8Ceri-23
7.14
0.21
Floyd
etal.,20
12Gen
istein
Anticancer,
PKI
2.5
HLM
Pacli
Burn
ettet
al.,20
11Glipizide
Antidiabe
tic,
sulfon
ylurea
338.2
rCYP2C
8Fluo
1.04
0.01
6,0.01
,0.01
Sch
elleman
etal.,20
14Glybu
ride
(glibe
nclam
ide)
Antidiab
etic,su
lfon
ylur
ea10
.8rC
YP2C
8Amo
0.21
40.00
20.04
,0.01
Walsk
yet
al.,20
05a
4.3
rCYP2C
8Ceri-1
0.10
,0.01
Floyd
etal.,20
126.7
rCYP2C
8Ceri-23
0.06
,0.01
Floyd
etal.,20
12Glyph
osate
Pesticide
82.0
HLM
Amo
Aba
sset
al.,20
09Hyd
roxy
methyl-iva
caftor
(M1)
Dru
gmetab
olite
17.7
0.39
Com
petitive
HLM
Amo
FDA,20
12g
Ibru
tinib
Anticanc
er,PKI
12.03
HLM
Pacli
0.37
0.12
70.03
,0.01
FDA,20
13d
Ibru
tinibmetab
olitePCI-
4522
7Dru
gmetab
olite
(7.84)
HLM
Pacli
FDA,20
13d
Iclapr
imAntibiotic
(91.5)
rCYP2C
8n/a
Hallet
al.,(200
7)ID
9515
51Acotiam
idean
alog
17HLM
DBF
Furu
taet
al.,20
04Idelalisib
Anticanc
er,PKI
13HLM
Pacli
4.6
,0.16
0.71
0.11
FDA,20
14h
(con
tinued
)
198 Backman et al.
TABLE
6—Con
tinued
Inhibitor
Therap
euticUse
and/or
Dru
gClass
IC50
Ki
Mod
eof
Inhibition
Test
System
Marke
rRea
ctiona
I maxb
f ub
I/Kic
I u/K
icReferen
ces
Idelalisib
metab
oliteGS-
5631
17Dru
gmetab
olite
39.8
HLM
Pacli
9.4
,0.12
0.47
0.06
FDA,20
14h
Imatinib
Anticancer,
PKI
15.7
8.4
Mixed
HLM
Amo
5.27
0.05
0.63
0.03
Filpp
ulaet
al.,20
1225
.9HLM
Pacli
0.41
0.02
Kim
etal.,20
13b
11.28
HLM
Pacli
0.47
0.02
Wan
get
al.,20
14a
Inda
caterol
Antiobs
truc
tive
,LABA
30HLM
Pacli
0.00
125
0.04
9,0.01
,0.01
FDA,20
11a
Indiplon
Sed
ative,
GABAA
receptor
mod
ulator
3015
HLM
Pacli
Mad
anet
al.,20
07
Indo
methacin
Anti-inflam
matory,
NSAID
88HLM
Amo
6.7
0.10
0.15
0.02
Jenk
inset
al.,20
11In
domethacin
acyl-b-D
-glucu
ronide
Dru
gmetab
olite
26HLM
Amo
Jenkinset
al.,20
11
Ipriflav
oneM1
Dru
gmetab
olite
9.9
HLM
Pacli
Moonet
al.,20
07Ipriflav
oneM2
Dru
gmetab
olite
10.2
HLM
Pacli
Moonet
al.,20
07Ipriflav
oneM4
Dru
gmetab
olite
31.8
HLM
Pacli
Moonet
al.,20
07Ipriflav
oneM5
Dru
gmetab
olite
2.5
HLM
Pacli
Moonet
al.,20
07Irbe
sartan
Antihyp
ertens
ive,
ARB
9.73
rCYP2C
8Amo
3.0
0.10
0.62
0.06
Walsk
yet
al.,20
05a
18rC
YP2C
8Ceri-1
0.33
0.03
Floyd
etal.,20
1216
rCYP2C
8Ceri-23
0.38
0.04
Floyd
etal.,20
12Isotretino
in(13-cis-retinoic
acid)
Antiacne
,retinoid
15.1
66.2
HLM
Taz
a0.69
,0.01
0.01
,0.01
Attar
etal.,20
03
Isradipine
Antihyp
ertens
ive,
CCB
5.00
HLM
Pacli
0.03
00.03
0.01
,0.01
Lee
etal.,20
12a
Itracona
zole
Antifunga
l31
rCYP2C
8Pacli
0.9
0.00
20.06
,0.01
Yoshida
etal.,20
12Ivacaftor
Antifibrotic
3.8
3.4
Mixed
HLM
Amo
13.89
,0.02
4.09
0.08
FDA,20
12g
Ivacaftormetab
olite(M
6)Dru
gmetab
olite
63.1
HLM
Amo
FDA,20
12g
Ketocon
azole
Antifung
al25
HLM
Pacli
3.2
0.01
0.26
,0.01
Mon
sarrat
etal.,19
972.5
Non
compe
titive
rCYP2C
8Torse
1.28
0.01
Ong
etal.,20
004.0
rCYP2C
8Dia
1.60
0.02
Sai
etal.,20
008.9
rCYP2C
8Phen
a0.72
,0.01
Sai
etal.,20
006-9
HLM
Pacli
1.07
0.01
Dierk
set
al.,20
0111
.8Non
compe
titive
HLM
Pacli
0.27
,0.01
Bun
etal.,20
0387
.7HLM
Amo
0.07
,0.01
Tur
peinen
etal.,20
055.51
rCYP2C
8Amo
1.16
0.01
Walsk
yet
al.,20
05a
4rC
YP2C
8Amo
1.60
0.02
O’Don
nellet
al.,20
072.45
HLM
Pacli
2.61
0.03
Lee
etal.,20
12a
1.7
HLM
Amo
3.77
0.04
Nirog
iet
al.,20
15Ketop
rofenacyl-b- D-
glucu
ronide
Dru
gmetab
olite
26HLM
Amo
Jenkinset
al.,20
11
KR-325
70Antiarrh
ythmic
30HLM
Pacli
Kim
etal.,20
06KR-604
36Antiulcerative,
PPI
30HLM
Pacli
Jiet
al.,20
05Lan
sopr
azole
Antiulcerative,
PPI
55rC
YP2C
8Ceri-1
0.67
10.03
0.02
,0.01
Floyd
etal.,20
1219
rCYP2C
8Ceri-23
0.07
,0.01
Floyd
etal.,20
125.75
HLM
Pacli
0.23
,0.01
Lee
etal.,20
12a
Lap
atinib
Antican
cer,
PKI
0.60
Com
petitive
HLM
Pacli
4.2
,0.01
7.00
,0.07
FDA,20
07e
1.43
HLM
Pacli
2.94
,0.03
Wan
get
al.,20
14a
Larop
iprant
Antias
thmatic,PGD2
receptor
antago
nist
6.5
n/a
n/a
Sch
wartz
etal.,20
09
Larom
ustine
(VNP40
101M
)Antican
cer,
alky
latingag
ent
.75
0Non
compe
titive
HLM
Amo
Nas
saret
al.,20
09
Las
ofox
ifen
eAntiosteopo
rotic,
SERM
8.1
HLM
Amo
0.00
50,0.01
Molleret
al.,20
06Len
vatinib
Antican
cer,
PKI
10.1
10.1
HLM
Pacli
1.54
60.02
0.15
,0.01
FDA,20
15a
Lestaurtinib
(CEP-701
)Anticanc
er,PKI
9.5
HLM
Amo
Filpp
ulaet
al.,20
14Lev
othyrox
ine
Hormon
alreplacem
ent
therap
y3.30
rCYP2C
8Amo
Walsk
yet
al.,20
05a
5.4
rCYP2C
8Ceri-1
Floyd
etal.,20
124.6
rCYP2C
8Ceri-23
Floyd
etal.,20
12 (con
tinued
)
Role of CYP2C8 in Drug Metabolism and Interactions 199
TABLE
6—Con
tinued
Inhibitor
Therap
euticUse
and/or
Dru
gClass
IC50
Ki
Mod
eof
Inhibition
Test
System
Marke
rRea
ctiona
I maxb
f ub
I/Kic
I u/K
icReferen
ces
Lop
eram
ide
Antidiarrh
eal,op
ioid
24HLM
Amo
0.00
42,0.01
Nirog
iet
al.,20
14Lop
inav
irAntiviral,pr
otea
seinhibitor
4.1
rCYP2C
8Amo
15.6
0.02
7.61
0.15
Parikhet
al.,20
07Loratad
ine
Antihistamine
3.36
rCYP2C
8Amo
0.00
880.03
,0.01
,0.01
Walsk
yet
al.,20
05a
2.95
HLM
Pacli
,0.01
,0.01
Lee
etal.,20
12a
Lorcaserin
Antiob
esity,
5-HT2Creceptor
agon
ist
.20
0HLM
Pacli
0.43
40.30
,0.01
,0.01
FDA,20
12b
Lorcaserinsu
lfam
ate(M
1)Dru
gmetab
olite
.20
0HLM
Pacli
FDA,20
12b
Losartan
Antihyp
ertens
ive,
ARB
12.9
rCYP2C
8Amo
0.64
0.01
30.10
,0.01
Walsk
yet
al.,20
05a
40.7
Com
petitive
rCYP2C
8Pacli
0.02
,0.01
Muka
iet
al.,20
14Lov
astatin(lactone
,pa
rent)
Antihyp
erlipide
mic,HMG-
CoA
redu
ctas
einhibitor
14.7
8.4
Mixed
HLM
Pacli
0.10
00.05
0.01
,0.01
Tornioet
al.,20
05
9.10
rCYP2C
8Amo
0.02
,0.01
Walsk
yet
al.,20
05a
79.9
HLM
Pacli
,0.01
,0.01
Sak
aeda
etal.,20
065.6
Com
petitive
HLM
Amo
0.02
,0.01
Van
denB
rink
etal.,20
119.3
Com
petitive
HLM
Mon
te0.01
,0.01
Van
denB
rink
etal.,20
1118
.8Com
petitive
HLM
Pacli
,0.01
,0.01
Van
denB
rink
etal.,20
112.8
Com
petitive
HLM
Rep
a0.04
,0.01
Van
denB
rink
etal.,20
114.2
Com
petitive
HLM
Rosi
0.02
,0.01
Van
denB
rink
etal.,20
1127
.5rC
YP2C
8Fluo
,0.01
,0.01
Sch
elleman
etal.,20
14Lov
astatinacid
Antihyp
erlipide
mic,HMG-
CoA
redu
ctas
einhibitor
54.9
48.9
Mixed
HLM
Pacli
0.01
10.05
,0.01
,0.01
Tornioet
al.,20
05
74.6
HLM
Pacli
,0.01
,0.01
Sak
aeda
etal.,20
06Maciten
tan
Antihyp
ertens
ive,
ERA
21HLM
Pacli
0.29
,0.01
0.03
,0.01
FDA,20
13k
Maciten
tanmetab
oliteM6
(ACT-132
577)
Dru
gmetab
olite
23HLM
Pacli
FDA,20
13k
Macrolactin
AAntibiotic
26.4
HLM
Rosi-OH
Bae
etal.,20
14Malathion
Pesticide
31.0
HLM
Amo
Aba
sset
al.,20
09Med
roxy
prog
esterone
Proge
stin
4.79
rCYP2C
8Amo
0.12
30.14
0.05
,0.01
Walsk
yet
al.,20
05a
0.76
Com
petitive
HLM
Amo
0.16
0.02
Van
denB
rink
etal.,20
117.5
Com
petitive
HLM
Mon
te0.02
,0.01
Van
denB
rink
etal.,20
118.2
Com
petitive
HLM
Pacli
0.02
,0.01
Van
denB
rink
etal.,20
111.9
Com
petitive
HLM
Rep
a0.07
,0.01
Van
denB
rink
etal.,20
116.6
Com
petitive
HLM
Rosi
0.02
,0.01
Van
denB
rink
etal.,20
11Mefen
amic
acid
Anti-inflammatory,
NSAID
14.9
HLM
Amo
41.44
,0.10
5.56
0.56
Jenk
inset
al.,20
11Mefen
amic
acyl-b- D-
gluc
uron
ide
Dru
gmetab
olite
8.5
HLM
Amo
Jenkinset
al.,20
11
Mertans
ine(D
M1)
Antibo
dy-dru
glink
er11
Com
petitive
HLM
Pacli
Dav
iset
al.,20
12Methox
salen(8-
methox
ypsoralen)
Antipsoriatic
;10
HLM
Pacli
2.36
;0.47
Dierk
set
al.,20
01
Methyl
belinostat
Dru
gmetab
olite
13.8
HLM
n/a
FDA,20
14c
Methy
lpredn
isolon
eAnti-inflammatory,
gluc
ucorticoid
25.4
rCYP2C
8Amo
0.47
50.22
0.04
,0.01
Walsk
yet
al.,20
05a
Midaz
olam
Sed
ative,
benz
odiazepine
18Non
compe
titive
rCYP2C
8Torse
0.34
0.02
0.02
,0.01
Onget
al.,20
0012
.4rC
YP2C
8Amo
0.06
,0.01
Walsk
yet
al.,20
05a
MMB4DMS
Antido
te,ch
olinergicag
onist
82.9
126
Non
compe
titive
rCYP2C
8Luc
iHon
get
al.,20
13Mom
etas
onefuroate
Anti-inflam
matory,
glucu
corticoid
0.81
3rC
YP2C
8Amo
0.00
012
0.02
,0.01
,0.01
Walsk
yet
al.,20
05a
0.32
7HLM
Amo
,0.01
,0.01
Walsk
yet
al.,20
05a
Mon
teluka
stAntias
thmatic,LTRA
0.00
922
rCYP2C
8Amo
0.89
,0.01
193.06
1.93
Walsk
yet
al.,20
05a
0.01
96HLM
Amo
90.82
0.91
Walsk
yet
al.,20
05a
0.00
92Com
petitive
rCYP2C
8Amo
96.74
0.97
Walsk
yet
al.,20
05b
0.01
9Com
petitive
rCYP2C
8Rosi
46.84
0.47
Walsk
yet
al.,20
05b
0.02
0–2.0
0.01
4Com
petitive
HLM
Amo
63.57
0.64
Walsk
yet
al.,20
05b
0.15
Com
petitive
HLM
Pacli
5.93
0.06
Walsk
yet
al.,20
05b
0.11
Com
petitive
HLM
Rosi
8.09
0.08
Walsk
yet
al.,20
05b
(con
tinued
)
200 Backman et al.
TABLE
6—Con
tinued
Inhibitor
Therap
euticUse
and/or
Dru
gClass
IC50
Ki
Mod
eof
Inhibition
Test
System
Marke
rRea
ctiona
I maxb
f ub
I/Kic
I u/K
icReferen
ces
0.18
HLM
Pio
9.89
0.10
Jaak
kola
etal.,20
06c
0.00
9–0.01
rCYP2C
8Amo
197.78
1.98
O’Don
nellet
al.,20
070.02
20.01
3HLM
Amo
68.46
0.69
Perloffet
al.,20
090.00
81Com
petitive
HLM
Amo
109.88
1.10
Van
denB
rink
etal.,20
110.02
6Com
petitive
HLM
Pacli
34.23
0.34
Van
denB
rink
etal.,20
110.01
6Com
petitive
HLM
Rep
a55
.63
0.56
Van
denB
rink
etal.,20
110.21
Com
petitive
HLM
Rosi
4.24
0.04
Van
denB
rink
etal.,20
111.2
rCYP2C
8Ceri-1
1.48
0.02
Floyd
etal.,20
120.02
rCYP2C
8Ceri-23
89.00
0.89
Floyd
etal.,20
120.05
–0.10
HLM
Amo
35.60
0.36
Kozak
aiet
al.,20
120.14
Com
petitive
HLM
Pacli
6.36
0.06
Kim
etal.,20
13b
0.16
Com
petitive
HLM
Amo
5.56
0.06
Kim
etal.,20
13b
2.67
HLM
Pacli
0.67
,0.01
Zhen
get
al.,20
130.27
n/a
n/a
6.59
0.07
Korzekw
a,20
1415
9Hep
Amo
0.01
,0.01
Kosugi
etal.,20
142.9
HLM
Rosi-OH
0.61
,0.01
Zhen
get
al.,20
140.10
1HLM
Pacli
17.62
0.18
FDA,20
14j
0.14
HLM
Amo
12.71
0.13
FDA,20
14j
0.01
0–0.75
HLM
Amo
178.00
1.78
Nirog
iet
al.,20
15Neb
ivolol
Antihyp
ertens
ive,
b1
receptor
blocke
r55
Non
compe
titive
HLM
Pacli
3.65
0.08
870.07
,0.01
FDA,20
07a
Nefaz
odon
eAntide
pressa
nt
23.2
rCYP2C
8Amo
4.70
,0.01
0.41
,0.01
Walsk
yet
al.,20
05a
Netupitant
Antiem
etic
50.43
HLM
Pacli
0.75
0.00
50.03
,0.01
FDA,20
14b
Netupitant
hydr
oxylation
metab
oliteM3
Dru
gmetab
olite
26.95
HLM
Pacli
FDA,20
14b
Netupitant
N-
demethy
lation
metab
oliteM1
Dru
gmetab
olite
4.74
HLM
Pacli
FDA,20
14b
Nicardipine
Antihyp
ertens
ive,
CCB
7.1
HLM
Pacli
0.17
0.02
0.02
,0.01
Nak
amura
etal.,20
051.56
HLM
Pacli
0.22
,0.01
Lee
etal.,20
12a
Nifed
ipine
Antihyp
ertens
ive,
CCB
9.66
rCYP2C
8Amo
0.14
0.04
0.03
,0.01
Walsk
yet
al.,20
05a
20-23
rCYP2C
8Amo
0.01
,0.01
O’Don
nellet
al.,20
0713
.53
rCYP2C
8Pacli
0.02
,0.01
Gao
etal.,20
102.4
Com
petitive
HLM
Amo
0.06
,0.01
Van
denB
rink
etal.,20
116.3
Com
petitive
HLM
Mon
te0.02
,0.01
Van
denB
rink
etal.,20
119.5
Com
petitive
HLM
Pacli
0.02
,0.01
Van
denB
rink
etal.,20
111.5
Com
petitive
HLM
Rep
a0.09
,0.01
Van
denB
rink
etal.,20
115.8
Com
petitive
HLM
Rosi
0.02
,0.01
Van
denB
rink
etal.,20
113.5
HLM
Amo
0.08
,0.01
Nirog
iet
al.,20
14Nilotinib
Anticanc
er,PKI
,1
0.23
6Com
petitive
HLM
Pacli
4.3
0.02
18.22
0.36
FDA,20
07c
0.61
Com
petitive
rCYP2C
8Amo
7.04
0.14
Kim
etal.,20
13b
0.10
Com
petitive
rCYP2C
8Pacli
43.00
0.86
Kim
etal.,20
13b
0.7
0.15
Com
petitive
HLM
Amo
28.67
0.53
Kim
etal.,20
13b
0.4
0.9
Com
petitive
HLM
Pacli
4.78
0.10
Kim
etal.,20
13b
7.5
HLM
Rosi-OH
1.15
0.02
Kim
etal.,20
13b
0.10
HLM
Pacli
43.00
0.86
Wan
get
al.,20
14a
Ninteda
nib
Anticancer,
PKI
.50
HLM
Pacli
0.02
80.02
2,0.01
,0.01
FDA,20
14d
Nystatin
Antifun
gal
12.7
rCYP2C
8Amo
Walsk
yet
al.,20
05a
Ombitasvir
(ABT-267
)Antiviral,NS5A
inhibitor
7.4
n/a
n/a
0.07
0,0.01
0.02
,0.01
FDA,20
14k
Orp
henad
rine
Mus
clerelaxa
nt
278.8
rCYP2C
8Dia
Sai
etal.,20
0024
9.1
rCYP2C
8Phen
aSai
etal.,20
0026
5HLM
Amo
Nirog
iet
al.,20
15Orteron
el(TAK-700
)Antican
cer,
antian
drog
en27
.7HLM
n/a
Luet
al.,20
12Osp
emifen
eAntidy
spareu
nia,SERM
36.4
HLM
Amo
3.16
,0.01
0.17
,0.01
FDA,20
13i;Turp
einen
etal.,20
13
(con
tinued
)
Role of CYP2C8 in Drug Metabolism and Interactions 201
TABLE
6—Con
tinued
Inhibitor
Therap
euticUse
and/or
Dru
gClass
IC50
Ki
Mod
eof
Inhibition
Test
System
Marke
rRea
ctiona
I maxb
f ub
I/Kic
I u/K
icReferen
ces
Oxy
butynin
Antich
olinergic
4.50
rCYP2C
8Amo
0.03
1,0.01
0.01
,0.01
Walsk
yet
al.,20
05a
Paclitaxe
l(tax
ol)
Antican
cer,
taxa
ne
14.9
30.0
Com
petitive
HLM
Taz
a0.85
0.12
0.03
,0.01
Attar
etal.,20
0313
.3rC
YP2C
8Amo
0.13
0.02
Walsk
yet
al.,20
05a
23–24
rCYP2C
8Amo
0.07
,0.01
O’Don
nellet
al.,20
075.4
Com
petitive
HLM
Amo
0.16
0.02
Van
denB
rink
etal.,20
1189
.8Com
petitive
HLM
Mon
te,0.01
,0.01
Van
denB
rink
etal.,20
116.5
Com
petitive
HLM
Rep
a0.13
0.01
6Van
denB
rink
etal.,20
1112
.0Com
petitive
HLM
Rosi
0.07
,0.01
Van
denB
rink
etal.,20
11Pas
ireotide
Hormon
altherap
y,somas
tatinan
alog
;50
HLM
Pacli
0.01
50.12
,0.01
,0.01
FDA,20
12h
Paz
opan
ibAnticancer,
PKI
10HLM
Pacli
132
,0.01
26.40
0.26
FDA,20
09d
3.72
HLM
Pacli
35.48
0.36
Wan
get
al.,20
14a
PF-562
,271
Anticancer,
PKI
23HLM
n/a
Ron
get
al.,20
08Phen
thoa
tePesticide
10.3
HLM
Amo
Aba
sset
al.,20
09Pioglitaz
one
Antidiabe
tic,
PPAR-g
agon
ist
9.38
1.69
Com
petitive
HLM
Pacli
3.8
,0.01
2.25
0.02
Sah
iet
al.,20
0311
.7rC
YP2C
8Amo
0.65
,0.01
Walsk
yet
al.,20
05a
6.6
Com
petitive
HLM
Amo
0.58
,0.01
Van
denB
rink
etal.,20
117.1
Com
petitive
HLM
Mon
te0.54
,0.01
Van
denB
rink
etal.,20
1137
.6Com
petitive
HLM
Pacli
0.10
,0.01
Van
denB
rink
etal.,20
113.8
Com
petitive
HLM
Rep
a1.00
0.01
Van
denB
rink
etal.,20
116.1
Com
petitive
HLM
Rosi
0.62
,0.01
Van
denB
rink
etal.,20
1114
rCYP2C
8Ceri-1
0.54
,0.01
Floyd
etal.,20
1216
rCYP2C
8Ceri-23
0.48
,0.01
Floyd
etal.,20
12Pitav
astatin(acid,
parent)
Antihyp
erlipide
mic,HMG-
CoA
redu
ctas
einhibitor
57.0
HLM
Pacli
0.02
960.00
5,0.01
,0.01
Sak
aeda
etal.,20
06
Pitav
astatinlacton
eAntihyp
erlipide
mic,HMG-
CoA
redu
ctas
einhibitor
50.5
HLM
Pacli
0.01
900.00
5,0.01
,0.01
Sak
aeda
etal.,20
06
Pon
atinib
Anticanc
er,PKI
6.1
3.05
n/a
n/a
0.16
10.00
080.05
,0.01
FDA,20
12e
Prasu
grel
Antithrombo
tic,
platelet
aggreg
ationinhibitor
.45
.2rC
YP2C
8DBF
1.37
,0.06
1Hag
iharaet
al.,20
08
Prasu
grel
active
metab
olite(R
–13
8727
)Dru
gmetab
olite
.45
.2rC
YP2C
8DBF
Hag
iharaet
al.,20
08
Prasu
grel
thiolacton
e(R
–95
913)
Dru
gmetab
olite
.50
.0rC
YP2C
8DBF
Hag
iharaet
al.,20
08
Prava
statin
(acid,
parent)
Antihyp
erlipide
mic,HMG-
CoA
redu
ctas
einhibitor
.10
0.50
Mixed
HLM
Pacli
0.08
50.57
,0.01
,0.01
Tornioet
al.,20
05
.10
0HLM
Pacli
,0.01
,0.01
Sak
aeda
etal.,20
06Prava
statin
lacton
eAntihyp
erlipide
mic,HMG-
CoA
redu
ctas
einhibitor
99.3
HLM
Pacli
Sak
aeda
etal.,20
06
Profeno
fos
Pesticide
84.0
HLM
Amo
Aba
sset
al.,20
09Prometha
zine
Sed
ative,
antihistam
ine
23HLM
Amo
0.07
0.07
,0.01
,0.01
Nirog
iet
al.,20
14Propo
xyph
ene
Analge
sic,
opioid
32rC
YP2C
8Ceri-1
Floyd
etal.,20
1218
rCYP2C
8Ceri-23
Floyd
etal.,20
12Prothiona
mide
Antitube
rculosis
57.6
HLM
Pacli
Shimok
awaet
al.,20
15Pyrim
etham
ine
Antimalarial
45.1
rCYP2C
8Amo
4.74
0.13
0.21
0.02
7Parikhet
al.,20
07Que
tiap
ine
Antipsych
otic
20HLM
Amo
0.31
40.17
0.03
,0.01
Nirog
iet
al.,20
14Quinidine
Antiarrh
ythmic
98.5
rCYP2C
8Dia
40.13
0.08
0.01
Sai
etal.,20
0013
5.4
rCYP2C
8Phen
a0.06
,0.01
Sai
etal.,20
0050
HLM
Pacli
0.16
0.02
Dierk
set
al.,20
01Quinine
Antim
alarial
11Com
petitive
rCYP2C
8Torse
290.15
2.64
0.40
Ong
etal.,20
00R48
3Antidiab
etic,P
PAR-g
agon
ist
5HLM
Pacli
Web
eret
al.,20
05Rab
eprazole
Antiulcerative,
PPI
12.0
rCYP2C
8Amo
0.9
0.03
70.15
,0.01
Walsk
yet
al.,20
05a
Ran
itidine
Antiulcerative,
H2R
A10
,000
HLM
Pacli
1.31
0.85
,0.01
,0.01
Mon
sarrat
etal.,19
973.1
HLM
Amo
0.85
0.72
Nirog
iet
al.,20
14Reg
orafen
ibAnticanc
er,PKI
1.7
0.6
n/a
n/a
8.1
0.00
513
.50
0.04
FDA,20
12i
(con
tinued
)
202 Backman et al.
TABLE
6—Con
tinued
Inhibitor
Therap
euticUse
and/or
Dru
gClass
IC50
Ki
Mod
eof
Inhibition
Test
System
Marke
rRea
ctiona
I maxb
f ub
I/Kic
I u/K
icReferen
ces
Reg
orafen
ibM2
Dru
gmetab
olite
1.0
n/a
n/a
FDA,20
12i
Reg
orafen
ibM5
Dru
gmetab
olite
1.3
n/a
n/a
FDA,20
12i
Rep
aglinide
Antidiabe
tic,
meg
litinide
analog
27.1
Com
petitive
HLM
Amo
0.10
40.02
6,0.01
,0.01
Van
denB
rink
etal.,20
11
11.1
Com
petitive
HLM
Mon
te,0.01
,0.01
Van
denB
rink
etal.,20
11.10
0Com
petitive
HLM
Pacli
,0.01
,0.01
Van
denB
rink
etal.,20
1123
.0Com
petitive
HLM
Rosi
,0.01
,0.01
Van
denB
rink
etal.,20
11Retinoicacid,all-tran
s(tretino
in)
Antiacne,
retinoid
27.0
Com
petitive
HLM
Pacli
1.15
,0.05
0.04
,0.01
Rah
man
etal.,19
94
Rifam
pin(rifam
picin)
Antibiotic
30.2
Com
petitive
HLM
Pacli
80.40
0.27
0.11
Kajosaa
riet
al.,20
05a
Rifap
entine
Antitube
rculosis
115
HLM
Pacli
34.21
0.02
0.59
0.01
Shimok
awaet
al.,20
15Rilpivirine
Antiviral,NNRTI
13.2–19
.110
.0HLM
Pacli
0.5
,0.01
0.05
,0.01
FDA,20
11d
Riton
avir
Antiviral,pr
otea
seinhibitor
3.03
rCYP2C
8Amo
150.02
9.90
0.20
Walsk
yet
al.,20
05a
1–2
rCYP2C
8Amo
30.00
0.60
O’Don
nellet
al.,20
075.5
HLM
Pacli
5.46
0.11
FDA,20
12j
Rofecox
ibAnti-inflam
matory,
NSAID
95rC
YP2C
8Ceri-1
1.02
0.13
0.02
,0.01
Floyd
etal.,20
1214
rCYP2C
8Ceri-23
0.15
0.02
Floyd
etal.,20
12Rosebe
nga
lXan
then
edy
e53
Hep
Amo
Kaz
miet
al.,20
14
Rosiglitazone
Antidiab
etic,P
PAR-g
agon
ist
18HLM
Pacli
1.7
0.00
20.19
,0.01
Baldw
inet
al.,19
999.58
5.59
Com
petitive
HLM
Pacli
0.30
,0.01
Sah
iet
al.,20
0324
.1–26
.3HLM
Pacli
0.13
,0.01
Kim
etal.,20
05b
10.8
rCYP2C
8Amo
0.13
,0.01
Walsk
yet
al.,20
05a
5.2
Com
petitive
HLM
Amo
0.33
,0.01
Van
denB
rink
etal.,20
114.1
Com
petitive
HLM
Mon
te0.42
,0.01
Van
denB
rink
etal.,20
1128
.6Com
petitive
HLM
Pacli
0.06
,0.01
Van
denB
rink
etal.,20
111.4
Com
petitive
HLM
Rep
a1.21
,0.01
Van
denB
rink
etal.,20
113.0
rCYP2C
8Ceri-1
1.13
,0.01
Floyd
etal.,20
122.7
rCYP2C
8Ceri-23
1.26
,0.01
Floyd
etal.,20
12Rosuva
statin
(acid,
parent)
Antihyp
erlipide
mic,HMG-
CoA
redu
ctas
einhibitor
.10
0.50
Mixed
HLM
Pacli
0.00
460.12
,0.01
,0.01
Tornioet
al.,20
05
.10
0HLM
Pacli
,0.01
,0.01
Sak
aeda
etal.,20
06Rosuv
astatinlacton
eAntihyp
erlipide
mic,HMG-
CoA
redu
ctas
einhibitor
9.8
HLM
Pacli
Fujinoet
al.,20
04
32.5
HLM
Pacli
Sak
aeda
etal.,20
06Salmeterol
Antias
thmatic,b-2-ag
onist
1.87
rCYP2C
8Amo
0.00
40,0.01
Walsk
yet
al.,20
05a
San
guinarine
Antican
cer
10.2
8.9
Non
compe
titive
HLM
Pacli
Qiet
al.,20
13Saq
uina
vir
Antiviral,pr
otea
seinhibitor
1.8
rCYP2C
8Amo
1.41
0.02
1.57
0.03
1Parikhet
al.,20
07Saracatinib
Antican
cer,
PKI
201.8
HLM
Amo
Filpp
ulaet
al.,20
14Sarizotan
Antips
ycho
tic
18.2
dCom
petitive
HLM
Pacli
0.91
0.05
Galleman
net
al.,20
10Satraplatin
(JM-216
)Antican
cer
1–3
0.9
Non
compe
titive
HLM
Pacli
And
oet
al.,19
98Seliciclib(R
-roscovitine
)Anticanc
er,PKI
119
rCYP2C
8DBF
100.10
0.17
0.02
McC
luean
dStuart,
2008
Sertraline
Antide
pressa
nt,SSRI
25.5
rCYP2C
8Amo
0.48
40.02
0.04
,0.01
Walsk
yet
al.,20
05a
350
HLM
Pacli
,0.01
,0.01
FDA,20
08b
.10
0Com
petitive
HLM
Amo
,0.01
,0.01
Van
denB
rink
etal.,20
119.0
Com
petitive
HLM
Mon
te0.05
,0.01
Van
denB
rink
etal.,20
11.10
0Com
petitive
HLM
Pacli
,0.01
,0.01
Van
denB
rink
etal.,20
117.8
Com
petitive
HLM
Rep
a0.06
,0.01
Van
denB
rink
etal.,20
118.1
Com
petitive
HLM
Rosi
0.06
,0.01
Van
denB
rink
etal.,20
1129
.7HLM
Pacli
0.03
,0.01
Erveet
al.,20
1315
HLM
Amo
0.06
,0.01
Nirog
iet
al.,20
14Sim
eprevir(TMC43
5)Antiviral,pr
otea
seinhibitor
(36.8)
HLM
n/a
14.5
,0.00
10.79
,0.01
FDA,20
13h
Sim
vastatin
(lactone
,pa
rent)
Antihyp
erlipide
mic,
HMG-C
oAredu
ctas
einhibitor
9.6
7.1
HLM
Pacli
0.09
60.06
0.01
,0.01
Tornioet
al.,20
05 (con
tinued
)
Role of CYP2C8 in Drug Metabolism and Interactions 203
TABLE
6—Con
tinued
Inhibitor
Therap
euticUse
and/or
Dru
gClass
IC50
Ki
Mod
eof
Inhibition
Test
System
Marke
rRea
ctiona
I maxb
f ub
I/Kic
I u/K
icReferen
ces
5.39
rCYP2C
8Amo
0.04
,0.01
Walsk
yet
al.,20
05a
44.1
HLM
Pacli
,0.01
,0.01
Sak
aeda
etal.,20
068.3
HLM
Amo
0.02
,0.01
Jenk
inset
al.,20
117.5
Com
petitive
HLM
Amo
0.01
,0.01
Van
denB
rink
etal.,20
115.7
Com
petitive
HLM
Mon
te0.02
,0.01
Van
denB
rink
etal.,20
1112
.3Com
petitive
HLM
Pacli
,0.01
,0.01
Van
denB
rink
etal.,20
111.1
Com
petitive
HLM
Rep
a0.09
,0.01
Van
denB
rink
etal.,20
113.3
Com
petitive
HLM
Rosi
0.03
,0.01
Van
denB
rink
etal.,20
113.70
HLM
Pacli
0.05
,0.01
Lee
etal.,20
12a
28rC
YP2C
8Fluo
,0.01
,0.01
Sch
elleman
etal.,20
14Sim
vastatin
acid
Antihyp
erlipide
mic,HMG-
CoA
redu
ctas
einhibitor
66.5
41.1
Mixed
HLM
Pacli
Tornioet
al.,20
05
51.5
HLM
Pacli
Sak
aeda
etal.,20
0676
.5rC
YP2C
8Fluo
Sch
elleman
etal.,20
14Sim
vastatin
acyl-b- D-
gluc
uron
ide
Dru
gmetab
olite
3.8
HLM
Amo
Jenkinset
al.,20
11
SIP
I535
7Antidep
ressan
t,Seroton
in-
norep
inep
hrine-do
pamine
reuptak
einhibitor
89.23
HLM
Pacli
Fan
etal.,20
15
Sitax
entan
Antihyp
ertensive
,ERA
1.58
HLM
Pacli
22.42
28.38
Erveet
al.,20
13Sorafen
ibAnticanc
er,PKI
1-2
rCYP2C
8Amo
21.5
0.01
21.50
0.22
FDA,20
05b
2.4
n/a
n/a
8.96
0.09
Flahe
rtyet
al.,20
111.59
HLM
Pacli
13.52
0.14
Wan
get
al.,20
14a
Spirono
lacton
eDiuretic
6.99
rCYP2C
8Amo
0.44
4,0.10
0.13
0.01
Walsk
yet
al.,20
05a
Stiripe
ntol
Antiepileptic
37.1
35Non
compe
titive
rCYP2C
8Carba
28.17
0.76
Caz
aliet
al.,20
03Sulfap
hen
azole
Antimicrobial
63Com
petitive
rCYP2C
8DTP
Man
cyet
al.,19
960.42
rCYP2C
8R-ibu
-2Ham
man
etal.,19
970.55
rCYP2C
8R-ibu
-3Ham
man
etal.,19
970.36
rCYP2C
8S-ibu
-2Ham
man
etal.,19
970.38
rCYP2C
8S-ibu
-3Ham
man
etal.,19
9750
5rC
YP2C
8Torse
Minerset
al.,20
0017
2.0
rCYP2C
8Dia
Sai
etal.,20
00.50
HLM
Pacli
Dierk
set
al.,20
01Sun
itinib
Anticancer,
PKI
28HLM
Pacli
0.21
0.05
,0.01
,0.01
FDA,20
06b
91.51
HLM
Pacli
,0.01
,0.01
Wan
get
al.,20
14a
Sunitinibmetab
olite
Su01
2662
Dru
gmetab
olite
52HLM
Pacli
FDA,20
06b
Suvo
rexa
nt
Sed
ative,
orex
inreceptor
antago
nist
15HLM
Pacli
0.96
,0.01
0.13
,0.01
FDA,20
14j
Suvo
rexa
ntM9
(L-002
0158
83)
Dru
gmetab
olite
37HLM
Amo
FDA,20
14j
Tam
oxifen
Anticancer,
SERM
3.34
rCYP2C
8Amo
0.32
3,0.02
0.19
,0.01
Walsk
yet
al.,20
05a
3–10
rCYP2C
8Amo
0.22
,0.01
O’Don
nellet
al.,20
073.1
Com
petitive
HLM
Amo
0.10
,0.01
Van
denB
rink
etal.,20
112.1
Com
petitive
HLM
Mon
te0.15
,0.01
Van
denB
rink
etal.,20
1112
.2Com
petitive
HLM
Pacli
0.03
,0.01
Van
denB
rink
etal.,20
1110
.1Com
petitive
HLM
Rep
a0.03
,0.01
Van
denB
rink
etal.,20
112.6
Com
petitive
HLM
Rosi
0.12
,0.01
Van
denB
rink
etal.,20
1114
.3HLM
Pacli
0.06
,0.01
Lee
etal.,20
12a
2.3
HLM
Amo
0.28
,0.01
Nirog
iet
al.,20
14Tan
espimycin
Anticanc
er29
HLM
Pacli
17.34
,0.10
1.20
0.12
Gan
etal.,20
12Tas
imelteon
Circadian
regu
lator
.10
0HLM
Amo
0.80
;0.10
0.02
,0.01
FDA,20
14m
Tas
imelteon
M12
Dru
gmetab
olite
.10
0HLM
Amo
FDA,20
14m
Teg
aserod
Gas
trop
rokine
tic,
5-HT4
receptor
agon
ist
;13
0HLM
Pacli
0.00
650.02
,0.01
,0.01
Vicke
rset
al.,20
01 (con
tinued
)
204 Backman et al.
TABLE
6—Con
tinued
Inhibitor
Therap
euticUse
and/or
Dru
gClass
IC50
Ki
Mod
eof
Inhibition
Test
System
Marke
rRea
ctiona
I maxb
f ub
I/Kic
I u/K
icReferen
ces
Telithr
omycin
Antibiotic
87rC
YP2C
8Pacli
2.7
0.30
0.06
0.02
Yoshida
etal.,20
12Tem
sirolimus
Anticancer,
PKI
27HLM
Pacli
0.57
0.02
FDA,20
07d
Terbinafine
Antifunga
l;15
0HLM
Pacli
3,0.01
Vicke
rset
al.,19
99Terfena
dine
Antihistamine
5Non
compe
titive
rCYP2C
8Torse
0.00
330.03
,0.01
,0.01
Onget
al.,20
0011
.5rC
YP2C
8Amo
,0.01
,0.01
Walsk
yet
al.,20
05a
19.1
HLM
Pacli
,0.01
,0.01
Erveet
al.,20
13Terifluno
mide
Immun
osupp
ressan
t,dr
ug
metab
olite
0.17
4–0.21
90.10
0-0.15
0Com
petitive
,mixed
HLM
Pacli
0.11
0.05
1.1
0.06
FDA,20
12l
Ticag
relor
Antithrombo
tic,
platelet
aggreg
ationinhibitor
.50
HLM
Pacli
1.3
,0.02
Zhou
etal.,20
11;FDA,
2011
bTicag
relormetab
oliteAR-
C12
4910
XX
Dru
gmetab
olite
43HLM
Pacli
FDA,20
11b
Ticlopidine
Antithrombo
tic,
platelet
aggreg
ationinhibitor
100
rCYP2C
82-TPE
30.02
0.06
,0.01
Ha-Duo
nget
al.,20
01
43.9
rCYP2C
8DBF
0.14
,0.01
Hag
iharaet
al.,20
0829
HLM
Amo
0.21
,0.01
Nirog
iet
al.,20
15Tipranav
irAntiviral,pr
otea
seinhibitor
2.1
rCYP2C
8Amo
94.8
,0.01
90.29
,0.90
Parikhet
al.,20
07Tolbu
tamide
Antidiabe
tic,
sulfon
ylur
ea2,37
0Mixed
HLM
Pacli
196
0.09
0.08
,0.01
Rah
man
etal.,19
94Trametinib
Anticanc
er,PKI
0.34
HLM
Rosi
0.03
20.03
80.19
0.01
FDA,20
13f
Tranylcypr
omine
Antide
pressa
nt,MAOI
26–35
HLM
Pacli
0.42
0.03
Dierk
set
al.,20
0112
.1rC
YP2C
8Amo
0.07
Walsk
yet
al.,20
05a
103–
113
rCYP2C
8Amo
,0.01
O’Don
nellet
al.,20
0711
.24
rCYP2C
8Pacli
0.07
Gao
etal.,20
1022
.5HLM
Amo
0.04
Nirog
iet
al.,20
15Triam
cinolon
eAnti-inflammatory,
glucocorticoid
19.3
rCYP2C
8Amo
Walsk
yet
al.,20
05a
32.5
Com
petitive
HLM
Amo
Van
denB
rink
etal.,20
1153
.1Com
petitive
HLM
Mon
teVan
denB
rink
etal.,20
11.10
0Com
petitive
HLM
Pacli
Van
denB
rink
etal.,20
1142
.5Com
petitive
HLM
Rep
aVan
denB
rink
etal.,20
1120
.4Com
petitive
HLM
Rosi
Van
denB
rink
etal.,20
11Triaz
olam
Sed
ative,
benz
odiazepine
25Non
compe
titive
rCYP2C
8Torse
0.01
30.09
9,0.01
,0.01
Onget
al.,20
00Trimethop
rim
Antim
icrobial,dihyd
rofolate
redu
ctas
einhibitor
75rC
YP2C
8Pacli
40.63
0.05
0.03
Wen
etal.,20
02
5432
Com
petitive
HLM
Pacli
0.13
0.08
Wen
etal.,20
0251
.529
.0Com
petitive
HLM
Rosi-OH
0.14
0.09
Hru
skaet
al.,20
0571
HLM
Pio
0.11
0.07
Jaak
kola
etal.,20
06c
40.6
rCYP2C
8Amo
0.20
0.12
Parikhet
al.,20
0734
.1Com
petitive
rCYP2C
8Pio
0.12
0.07
Tornioet
al.,20
08b
38.2
Com
petitive
HLM
Pio
0.10
0.07
Tornioet
al.,20
08b
9.2
Com
petitive
HLM
Amo
0.43
0.27
Van
denB
rink
etal.,20
11.10
0Com
petitive
HLM
Mon
te,0.04
,0.03
Van
denB
rink
etal.,20
11.10
0Com
petitive
HLM
Pacli
,0.04
,0.03
Van
denB
rink
etal.,20
118.5
Com
petitive
HLM
Rep
a0.47
0.30
Van
denB
rink
etal.,20
1113
.2Com
petitive
HLM
Rosi
0.30
0.19
Van
denB
rink
etal.,20
114.5–
17HLM
Amo
1.78
1.12
Dinge
ret
al.,20
1412
2Hep
Amo
0.07
0.04
Kosugi
etal.,20
1417
.41–
20.38
HLM
Pacli
0.46
0.29
Pen
get
al.,20
15Troglitaz
one
Antidiabe
tic,
PPAR-g
agon
ist
1–5
0.3
Com
petitive
rCYP2C
8Pacli
3,0.01
10.00
,0.10
Yam
azak
iet
al.,20
0015
–20
HLM
Pacli
0.30
,0.01
Yam
azak
iet
al.,20
002.33
2.59
Com
petitive
HLM
Pacli
1.16
0.01
Sah
iet
al.,20
039.78
rCYP2C
8Pacli
0.61
,0.01
Gao
etal.,20
10Troglitaz
oneM1
Dru
gmetab
olite
9–41
rCYP2C
8Pacli
Yam
azak
iet
al.,20
00Troglitaz
oneM3
Dru
gmetab
olite
6-26
3.0
Com
petitive
rCYP2C
8Pacli
Yam
azak
iet
al.,20
0039
–.50
HLM
Pacli
Yam
azak
iet
al.,20
00
(con
tinued
)
Role of CYP2C8 in Drug Metabolism and Interactions 205
TABLE
6—Con
tinued
Inhibitor
Therap
euticUse
and/or
Dru
gClass
IC50
Ki
Mod
eof
Inhibition
Test
System
Marke
rRea
ctiona
I maxb
f ub
I/Kic
I u/K
icReferen
ces
Trolean
domycin
Antibiotic
953.0
rCYP2C
8Phe
na3
,0.01
Sai
etal.,20
00TSAHC
Antican
cer
1.0
0.81
Non
compe
titive
HLM
Amo
Imet
al.,20
12Ulipr
istal
Con
tracep
tive
,pr
ogesterone
receptor
mod
ulator
2.6
HLM
Pacli
0.03
7,0.06
0.03
,0.01
FDA,20
10b
UTL-5g
Chem
oprotective,
TNF-a
inhibitor
61.2
HLM
Rosi-OH
Wuet
al.,20
14
Valde
coxib
Anti-inflammatory,
NSAID
15.0
rCYP2C
8Amo
0.51
20.02
0.07
,0.01
Walsk
yet
al.,20
05a
Vem
urafenib
Anticancer,
PKI
12HLM
n/a
125
,0.01
20.9
0.21
EMA,20
12d
Vidupipr
ant(A
MG
853)
Antias
thmatic,PGD2
receptor
antago
nist
1.8
Bipha
sic
HLM
Mon
teFotiet
al.,20
12
5.4
1.1
Com
petitive
HLM
Pacli
Fotiet
al.,20
126.0
Com
petitive
HLM
Rosi
Fotiet
al.,20
12Vidupipr
antacyl
glucu
ronide(M
1)Dru
gmetab
olite
7.3
Bipha
sic
HLM
Mon
teFotiet
al.,20
12
2.7
Mixed
HLM
Pacli
Fotiet
al.,20
126.9
Mixed
HLM
Rosi
Fotiet
al.,20
12Vilaz
odon
eAntide
pressa
nt,SSRI
1.8
0.46
Com
petitive
HLM
Pacli
0.33
0.04
0.72
0.03
FDA,20
11g
Vinblas
tine
Anticancer
100
HLM
Pacli
Mon
sarrat
etal.,19
97Vincristine
Antican
cer
8HLM
Pacli
0.43
0.11
Mon
sarrat
etal.,19
97Vismod
egib
(GDC-044
9)Anticanc
er,SMO
Antago
nist
6.0
Non
compe
titive
HLM
Pacli
16.4
0.01
2.73
0.03
Won
get
al.,20
09;
LoR
usso
etal.,20
13Vorap
axar
Antithrombo
tic,
platelet
aggreg
ationinhibitor
1.5
0.86
Mixed
HLM
n/a
0.05
270.00
20.06
,0.01
Chen
etal.,20
14,FDA,
2014
lVortiox
etine
Antide
pressa
nt,SMS
9.34
HLM
n/a
0.04
724
0.02
,0.01
,0.01
FDA,20
13j
Vortiox
etinemetab
oliteLu
AA34
443
Dru
gmetab
olite
4.24
HLM
n/a
FDA,20
13j
Zafirluka
stAntiasthm
atic,LTRA
0.64
4rC
YP2C
8Amo
0.29
5,0.01
0.92
,0.01
Walsk
yet
al.,20
05a
0.38
8HLM
Amo
1.52
0.02
Walsk
yet
al.,20
05a
0.78
HLM
Pio
0.76
Jaak
kola
etal.,20
06c
.10
0Hep
Amo
,0.01
,0.01
Kosugi
etal.,20
140.01
4HLM
Amo
42.14
0.42
Nirog
iet
al.,20
14
3-ASBA,3-(anilinosulfon
yl)-be
nzenecarbo
xylic
acid;5-HT,5-hyd
roxy
tryp
tamine
(seroton
in);
5-MeO
-DIP
T,5-methox
y-N,N
-diisopr
opyltryp
tamine;
ARB,an
gioten
sin
IIreceptor
blocke
r;BTFM
gemfibrozil,5-(2,5-bis
(trifluo
romethyl)phen
oxy)-2,2-dim
ethylpe
ntanoicacid;C
CB,calcium
chan
nel
blocke
r;CP-778
875;
5-(N
-(4-((4-ethy
lben
zyl)thio)phe
nyl)su
lfam
oyl)-2-m
ethy
lben
zoic
acid;E
RA,e
ndothe
linreceptor
antago
nist;f
u,fractionun
boundin
plas
ma;
GABA,g
-aminob
utyricacid;H
2RA,H
-2receptor
antago
nist;HLM,h
uman
live
rmicrosomes;H
MG-C
oA,3
-hyd
roxy
-3-m
ethylglutaryl-coen
zymeA;I
C50,inhibitor
concentrationsu
pportinghalfof
themax
imal
inhibition;
I max,
peak
inhibitor
conc
entration
inplas
ma;
Ki,reve
rsible
inhibition
constan
t;LABA,long-actingb-adr
enocep
torag
onist;
LTRA,leuko
trienereceptor
antago
nist;
MAO,mon
oamineox
idas
e;MMB4DMS,1,19-m
ethylen
ebis
[4-[(hyd
roxy
imino)methy
l]-pyridinium]dimethan
esulfon
ate;
c-mpl,mye
lopr
oliferativeleuk
emia;n/a,
notav
ailable;
NNRTI,
nonn
ucleosidereve
rsetran
scriptas
einhibitor;NS,non
stru
cturalpr
otein;NSAID
,non
steroida
lan
ti-
inflam
matorydr
ug;
PDE,ph
osph
odiesteras
e;PGD2,
prostaglan
din
D2;
PKI,
protein
kinas
einhibitor;PPAR,pe
roxisomepr
oliferator-activated
receptor;PPI,
proton
pumpinhibitor;rC
YP2C
8,recombinan
tCYP2C
8;SERM,
selectiveestrog
enreceptor
mod
ulator;SGLT,sod
ium-glucose
linke
dtran
sporter;SMO,smoo
then
edreceptor;S
MS,seroton
inmod
ulatoran
dstim
ulator;SNRI,serotonin-norep
inep
hrinereup
take
inhibitor;S
SRI,selectiveserotonin
reuptak
einhibitor;TNF,tumor
necrosisfactor;TSAHC,4
-(p-toluen
esulfon
ylam
ido)-4-hyd
roxy
chalcone;
XO,x
anthineox
idas
e;UTL-5g,
N-(2,4-dich
loroph
enyl)-5-methy
l-1,2-ox
azole-3-carbox
amide.
a2-TPE,2-aroy
lthioph
en5-hyd
yrox
ylation;Ami,am
inop
yrineN-dem
ethylation;Amo,
amod
iaqu
ineN-dee
thylation;Carba
,carbam
azep
ine10
,11-ep
oxidation;Ceri-1,
ceriva
statin
demethylation
(M-1);
Ceri-23
,ceriva
statin
6-hyd
roxy
lation
(M-23);D
BF,d
iben
zylfluorescein
(fluorescentreaction
);Dia,diaz
epam
N-dem
ethylation;D
TP,2
,3-dichloro-4(2-then
oyl)ph
enol
5-hyd
roxy
lation
;Fluo,
fluorom
etricreaction
;R-ibu
-2,R
-ibu
profen
2-hyd
roxy
lation
;R-ibu
-3,R
-ibu
profen
3-hyd
roxy
lation
;S-ibu
-2,S
-ibu
profen
2-hyd
roxy
lation
;S-ibu
-3,S
-ibu
profen
3-hyd
roxy
lation
;Luci,luciferin-6
methyl
ether
demethylation(luminog
enicreaction
);Mon
te,m
onteluka
st36
-hyd
roxy
lation
;Mon
te-4,
form
ationof
mon
teluka
stmetab
olite4;
Pacli,p
aclitaxe
l6a-hyd
roxy
lation
;Phen
a,ph
enan
threnehyd
roxy
lation
;Pio,p
ioglitaz
onehyd
roxy
lation
(M-IV);Rep
a,repa
glinide39-hyd
roxy
lation
;Rosi,rosiglitaz
oneN-dem
ethylation;R
osi-
OH,rosiglitaz
onep-hyd
roxy
lation
;Taz
a,taza
rotenic
acid
sulfox
idation;
Tolbu
,tolbutamidemethy
lhyd
roxy
lation
;Torse,torsemidemethylhyd
roxy
lation
.bThis
inform
ationis
prim
arilyba
sedon
inform
ationfrom
theUW
Metab
olism
andTransp
ortDru
gIn
teractionDatab
ase(D
IDB),Cop
yrightUniversity
ofWas
hington
1999
-201
5(D
IDB
accessed
May
-Sep
tembe
r,20
15),an
dseconda
rily
oninform
ationfrom
Martinda
le:TheCom
pleteDru
gReferen
ce.Lon
don:Pharmaceu
ticalPress
(electronic
version),Tru
venHea
lth
Analytics(H
ealthcare),Green
woo
dVillage
,Colorad
o.Ava
ilab
leat:http://w
ww.
micromed
exsolution
s.com/(Martinda
leaccessed
June-Sep
tembe
r,20
15).In
case
seve
ralva
lues
wererepo
rted
forI m
axan
df u,thehighestva
lues
wereselected
.c W
hen
expe
rimen
tallyde
term
ined
Kiwas
not
available,
Kiwas
calculatedas
IC50/2.A
nI/Ki.
1.0indicatesthat
aclinically
releva
ntinhibitionis
like
ly,I/K
i=0.1–
1indicatesthat
aclinically
releva
ntinhibition
ispo
ssible,I/K
i,
0.1indicatesthat
aclinically
releva
ntinhibitionis
unlike
ly.
dUnbo
undva
lue.
206 Backman et al.
TABLE 7Natural and endogenous compounds that act as reversible CYP2C8 inhibitors
Inhibitor Description IC50 KiMode ofInhibition
TestSystem
MarkerReactiona References
mM (mg/ml) mM (mg/ml)
3-Isomangostin Constituent ofmangosteen
0.64 0.66 Competitive HLM Pacli Foti et al., 2009
6-Gingerol Constituent of gingerroot
(6.5) HLM Amo Mukkavilli et al., 2014
6-Prenylnaringenin Prenylflavonoid 1.9 HLM Amo Yuan et al., 20146-Shogaol Constitutent of ginger
root(0.8) HLM Amo Mukkavilli et al., 2014
8-Desoxygartanin Constituent ofmangosteen
1.85 2.80 Competitive HLM Pacli Foti et al., 2009
8-Gingerol Constituent of gingerroot
(0.7) HLM Amo Mukkavilli et al., 2014
8-Prenylnaringenin(flavaprenin)
Prenylflavonoid 0.6 HLM Amo Yuan et al., 2014
9-Hydroxycalabaxanthone Constituent ofmangosteen
14.1 HLM Pacli Foti et al., 2009
10-Gingerol Constituent of gingerroot
(0.7) HLM Amo Mukkavilli et al., 2014
11-Keto-b-boswellic acid Triterpene 9.5 HLM Pacli Frank and Unger, 2006Acetyl-a-boswellic acid Triterpene 65.8 HLM Pacli Frank and Unger, 2006Acetyl-b-boswellic acid Triterpene 33.4 HLM Pacli Frank and Unger, 2006Acetyl-11-keto-b-boswellic
acidTriterpene 10.1 HLM Pacli Frank and Unger, 2006
Allocryptopine Alkaloid 10-100 rCYP2C8 DBF Salminen et al., 2011Arachidonic acid Endogenous
compound7 Competitive rCYP2C8 Pacli Yamazaki and Shimada,
1999b-Boswellic acid Triterpene 8.7 HLM Pacli Frank and Unger, 2006Bo-yang-hwan-o-tang Oriental herbal
medicine(17,209) HLM Pacli Lee et al., 2012b
BST204 Dry extract of ginseng (17.4) HLM Rosi Zheng et al., 2014Capnoidine Alkaloid 10-100 rCYP2C8 DBF Salminen et al., 2011Cedrol Sesquiterpene 41.0 HLM Amo Jeong et al., 2014Corybulbine Alkaloid 10-100 rCYP2C8 DBF Salminen et al., 2011Corycavamine Alkaloid 10-100 rCYP2C8 DBF Salminen et al., 2011Corycavidine Alkaloid 10-100 rCYP2C8 DBF Salminen et al., 2011Corydaline Alkaloid 10-100 rCYP2C8 DBF Salminen et al., 2011Corypalmine Alkaloid 10-100 rCYP2C8 DBF Salminen et al., 2011Cranberry (powder) Natural product (24.7) HLM Amo Albassam et al., 2015
(24.0) HLM Pio Albassam et al., 2015Cryptopine Alkaloid 10-100 rCYP2C8 DBF Salminen et al., 2011b-Cryptoxanthin Carotenoid pigment 13.8 HLM Pacli Zheng et al., 2013Cudratricusxanthone Constituent of
Cudraniatricuspidata
4.69 2.2 Noncompetitive HLM Pacli Sim et al., 2015
Curcumin Diarylheptanoid 129.7 rCYP2C8 DBF Mach et al., 2010DA-9801 Extract (449.9) HLM Amo Ji et al., 2013Dioscorea nipponica Extract (237.1) HLM Amo Ji et al., 2013Diosmetin Flavonoid 3.13 Mixed HLM Pacli Quintieri et al., 2011Ellagic acid Constitutent of guava
leaf(13.99) rCYP2C8 DBF Kaneko et al., 2013
(2)-Epigallocatechin-3-gallate
Catechin 10.9 6.8 Competitive HLM Amo Misaka et al., 2013
Eupatilin Flavone 104.9 101.9 Competitive HLM Amo Ji et al., 2010Feverfew herb Natural product (104–126) rCYP2C8 Pacli Unger and Frank, 2004Fisetin Flavonol 10.8 1.3–6.0 Mixed HLM Pacli Václavíková et al., 2003Gartanin Constituent of
mangosteen6.28 HLM Pacli Foti et al., 2009
Ginger extract Extract (122.5) HLM Amo Mukkavilli et al., 2014Green tea extract Extract (4.5) HLM Amo Misaka et al., 2013Guava leaf extract Extract (18.16) rCYP2C8 DBF Kaneko et al., 2013Guava leaf polyphenol Constitutent of guava
leaf(1.45) rCYP2C8 DBF Kaneko et al., 2013
Gypenosides Oriental herbalmedicine
(20.06) HLM Pacli He et al., 2013
Hesperedin Flavonoid 274.7 rCYP2C8 Tolbu Pang et al., 2012Hesperetin Flavonoid 68.5 HLM Pacli Quintieri et al., 2011
168.4 rCYP2C8 Tolbu Pang et al., 2012Hibiscus sabdariffa
extractExtract (424) HLM Amo Johnson et al., 2013
Honey Natural product (102.9) (50.5) Competitive rCYP2C8 Amo Muthiah et al., 2012Honokiol Constituent of
Magnolia8.9 4.9 Competitive HLM Amo Jeong et al., 2013
Horsetail Natural product (93.0) HLM Amo Sevior et al., 2010
(continued )
Role of CYP2C8 in Drug Metabolism and Interactions 207
TABLE 7—Continued
Inhibitor Description IC50 KiMode ofInhibition
TestSystem
MarkerReactiona References
Hops extract Extract 0.8 HLM Amo Yuan et al., 2014Hunnemannine Alkaloid 1–10 rCYP2C8 DBF Salminen et al., 2011Hyperforin Constituent of
St. John’s Wort56 HLM Amo Hokkanen et al., 2011
Hypoxis hemerocallideaextract
Extract (192) HLM Pacli Fasinu et al., 2013a
Isocorybulbine Alkaloid 10–100 rCYP2C8 DBF Salminen et al., 2011Isoxanthohumol Prenylflavonoid 0.2 HLM Amo Yuan et al., 2014Jaceosidin Flavone 106.4 109.4 Competitive HLM Amo Ji et al., 2010Labisia pumila extracts Extracts (2.39–352.3) (0.70-33.9) Noncompetitive,
mixedrCYP2C8 DBF Pan et al., 2012
b-Lapachone Quinone 3.8 HLM Pacli Kim et al., 2013aLiquorice extract Extract (14.36–17.06) HLM Amo Li et al., 2015Liquorice root Natural product (22.6) HLM Amo Sevior et al., 2010Luteolin Flavonoid 82.0 rCYP2C8 Tolbu Pang et al., 2012a-Mangostin Constituent of
mangosteen0.88 0.64 Competitive HLM Pacli Foti et al., 2009
b-Mangostin Constituent ofmangosteen
8.39 HLM Pacli Foti et al., 2009
Mecambridine Alkaloid 10–100 rCYP2C8 DBF Salminen et al., 2011Milk thistle extract Extract (8.35) Mixed HLM Pacli Doehmer et al., 2011Morin Flavonol 17.3 7.3-12.3 Mixed HLM Pacli Václavíková et al., 2003Nantenine Alkaloid 1–10 rCYP2C8 DBF Salminen et al., 2011a-Naphthoflavone Flavone derivative 0.36 HLM Amo Nirogi et al., 2015Obovatol Constituent of
Magnolia11.1 HLM Amo Joo et al., 2013
Quercetin Flavonoid 1.29 Competitive rCYP2C8 Pacli Rahman et al., 19941.14 Competitive HLM Pacli Rahman et al., 1994
7 HLM Pacli Dierks et al., 20011.96-2.35 Competitive rCYP2C8 Amo Li et al., 2002
1.56 Competitive HLM Amo Li et al., 20022.47 rCYP2C8 DBF Yamamoto et al., 20024.07 19.7 HLM Taza Attar et al., 2003
10.1 Competitive HLM Pacli Bun et al., 200320.6 HLM DBF Ghosal et al., 20033.3 HLM Pacli Cai et al., 20046.3 HLM Pacli Donato et al., 20042.9 THLE DBF Donato et al., 200429.5 THLE Pacli Donato et al., 2004
3.9–6.2 rCYP2C8 Pacli Unger and Frank, 20043.33 rCYP2C8 Amo Walsky and Obach,
20043.06 HLM Amo Walsky and Obach,
20047.19–8.47 HLM Pacli Kim et al., 2005b
57.8 HLM Amo Turpeinen et al., 20053.94 rCYP2C8 Amo Walsky et al., 2005a
3.3–5.6 rCYP2C8 Amo O’Donnell et al., 20071.6 rCYP2C8 DBF McClue and Stuart,
20085.28–5.38 rCYP2C8 Pacli Gao et al., 2010
1.33 rCYP2C8 Bomcc Liu et al., 2010a0.029 HLM Amo Teng et al., 20100.49 Competitive HLM Amo VandenBrink et al.,
20110.52 Competitive HLM Monte VandenBrink et al.,
20113.0 Competitive HLM Pacli VandenBrink et al.,
20110.61 Competitive HLM Repa VandenBrink et al.,
20110.61 Competitive HLM Rosi VandenBrink et al.,
20114.20 2.07 Competitive rCYP2C8 Amo Muthiah et al., 20121.39 HLM Pacli Lee et al., 2012a46.0 rCYP2C8 Tolbu Pang et al., 201218.7 HLM Pacli Bymaster et al., 2013(0.59) rCYP2C8 DBF Kaneko et al., 2013
(0.3702) HLM Amo Mukkavilli et al., 201424.5 rcCYP2C8 DBF Pan et al., 201412.3 HLM Rosi-OH Wu et al., 2014
3.40–5.92 HLM Amo Li et al., 20151.2 HLM Amo Nirogi et al., 2015
Piperlonguminine Alkaloid 76.2 HLM Amo Song et al., 2014b
(continued )
208 Backman et al.
and organic anion transporter (OAT) 3 (Ki = 6.8 mM)(Schneck et al., 2004; Shitara et al., 2004; Nakagomi-Hagihara et al., 2007). The strong interactions betweengemfibrozil and CYP2C8 substrate drugs observed invivo are mainly due to its glucuronide metabolite(Ogilvie et al., 2006). Gemfibrozil 1-O-b glucuronideaffects CYP2C8 by mechanism-based inhibition (sec-tions V.B and VI.B).In vitro, the thiazolidinedione drugs pioglitazone,
rosiglitazone, and troglitazone are potent, competitiveinhibitors of CYP2C8with IC50 andKi values of,40mM(Table 6). However, e.g., pioglitazone does not affectCYP2C8 in vivo, likely because of its extensive proteinbinding (Kajosaari et al., 2006a).The antiviral agents atazanavir and efavirenz inhibit
CYP2C8 in vitro with Ki values of 2.1 and 4.8 mM,respectively [inhibitor concentration (I) to Ki ratios(I/Ki) = 3.7 and 6.3, respectively] (Table 6). In vivo,atazanavir has slightly affected the pharmacokineticsof rosiglitazone (FDA, 2015b). According to predictions,efavirenz may increase the area under the plasmaconcentration-time curve (AUC) of CYP2C8 substratesby more than fourfold at steady state, and such effectshave been observed in vivo (German et al., 2007).The immunosuppressant teriflunomide inhibits
CYP2C8 with a very low Ki of 0.10–0.15 mM (FDA,2012a). Thus, its estimated I/Ki ratio of 1.1 indicatesthat interactions between teriflunomide and CYP2C8substrate drugs are likely, in agreement with in vivofindings (section IV.C.2).Numerous protein kinase inhibitors inhibit CYP2C8
to various degrees in vitro (Table 6). However, for themost part, their in vivo inhibitory effects on CYP2C8have not been studied. For those whose inhibition hasbeen examined in a clinical setting, it seems to be rather
small/moderate. For instance, axitinib inhibits CYP2C8in vitro with aKi of 0.2–0.5 mM (I/Ki = 0.3–0.9), but it didnot alter paclitaxel plasma concentrations in patients(FDA, 2012f; Wang et al., 2014a). Similarly, cabozanti-nib is a noncompetitive inhibitor of CYP2C8 in vitro(Ki = 4.6 mM, I/Ki = 0.7), but the in vivo pharmacokineticsof rosiglitazone was not affected by cabozantinib (FDA,2012c; Nguyen et al., 2015). The inhibition of CYP2C8by pazopanib (Ki of 3.7 mM, I/Ki = 35) may be of clinicalrelevance (FDA, 2009d; Tan et al., 2014; Wang et al.,2014b). Nilotinib is a strong competitive CYP2C8 in-hibitor in vitro (Ki = 0.1–0.9 mM, I/Ki = 4.8–43), but italso induces CYP2C8 (FDA, 2007c). Hence, a clinicalinteraction study with a CYP2C8 probe substrate hasbeen recommended by the FDA to evaluate the in vivoeffect on CYP2C8 activity by nilotinib. Similarly, aninteraction study with a CYP2C8 substrate drug hasalso been recommended for regorafenib, which inhibitsCYP2C8 with a Ki value of 0.6 mM in vitro (I/Ki = 13.5)(FDA, 2012i). In addition, sorafenib seems to be a strongCYP2C8 inhibitor in vitro with Ki values, 3 mM (I/Ki =9–22) (Table 6), but the effect of sorafenib on CYP2C8in vivo has not been evaluated.
Also several other anticancer agents exhibit inhibi-tion of CYP2C8 in vitro (Table 6). For instance, theandrogen receptor antagonist enzalutamide is both asubstrate and inhibitor of CYP2C8 in vitro (Ki = 5.5 mM,I/Ki = 6.5) (FDA, 2012k). Vismodegib, an oral hedgehogpathway inhibitor, inhibits CYP2C8 in vitro with aKi of6.0 mM (I/Ki = 2.7), but vismodegib at steady state didnot affect the pharmacokinetics of rosiglitazone (Wonget al., 2009; LoRusso et al., 2013).
The iron chelator deferasirox inhibits CYP2C8 withan IC50 of 100 mM (I/Ki ,0.01) (FDA, 2005a), but it hasincreased repaglinide AUC by 2.3-fold in vivo (Skerjanec
TABLE 7—Continued
Inhibitor Description IC50 KiMode ofInhibition
TestSystem
MarkerReactiona References
Reserveratrol Stilbenoid 26.5 16.2–20.7 HLM Pacli Václavíková et al., 2003Saw palmetto Natural product (8) HLM Amo Sevior et al., 2010
(15.4) HLM Amo Albassam et al., 2015(9.6) HLM Pio Albassam et al., 2015
Scoulerine Alkaloid 10-100 rCYP2C8 DBF Salminen et al., 2011Star fruit (averrhoa
carambola) juiceFruit juice 2.2b HLM Pacli Zhang et al., 2007b
Sutherlandia frutescens Herb (22.4) HLM Pacli Fasinu et al., 2013bTanshinol borneol ester Combination of the
natural compoundsdanshensu andborneol
105 rCYP2C8 Bomcc Liu et al., 2010b
Thalictricavine Alkaloid 10–100 rCYP2C8 DBF Salminen et al., 2011Thelephoric acid Antioxidant 24.6 HLM Amo Song et al., 2014aTiliroside Flavonoid 12.1 9.4 Competitive HLM Pacli Sun et al., 2010Tualang honey Natural product (102.9) (50.5) Competitive rCYP2C8 Amo Muthiah et al., 2012Valerian Natural product (523.3) HLM Amo Sevior et al., 2010Xanthohumol Natural product 1.1 HLM Amo Yuan et al., 2014
HLM, human liver microsomes; IC50, inhibitor concentration supporting half of the maximal inhibition; Ki, reversible inhibition constant; n/a, not available; rcCYP2C8,reconstituted CYP2C8; rCYP2C8, recombinant CYP2C8; THLE, immortalized human liver epithelial cells.
aAmo, amodiaquine N-deethylation; Bomcc, flurogenic substrate; DBF, dibenzylfluorescein; Monte, montelukast 36-hydroxylation; Pacli, paclitaxel 6a-hydroxylation; Pio,pioglitazone hydroxylation (M-IV); Repa, repaglinide 39-hydroxylation; Rosi, rosiglitazone N-demethylation; Rosi-OH, rosiglitazone p-hydroxylation; Taza, tazarotenic acidsulfoxidation; Tolbu, tolbutamide methyl hydroxylation.
b% (v/v).
Role of CYP2C8 in Drug Metabolism and Interactions 209
et al., 2010). Febuxostat, a xanthine oxidase inhibitor,inhibits CYP2C8 in vitro with a Ki of 20 mM, suggestingthat the inhibition may be of clinical relevance (I/Ki =0.8). However, febuxostat at steady state had no effecton the concentrations of a single dose of rosiglitazone invivo (Naik et al., 2012). Similarly, rosiglitazone phar-macokineticswas not affected by the platelet aggregationinhibitor vorapaxar in vivo (Ki = 0.86 mM, I/Ki = 0.06)(Chen et al., 2014; FDA, 2014l).Sulfaphenazole, ketoconazole, diethyldithiocarba-
mate, methoxsalen (8-methoxypsoralen), and tranylcy-promine, commonly used as in vitro inhibitors ofCYP2C9, CYP3A4, CYP2E1, CYP2A6, and CYP2C19,respectively, also inhibit CYP2C8 in vitro (Table 6). Forinstance, sulfaphenazole is a strong competitive in-hibitor of CYP2C9 with a Ki of 0.3 mM, whereas its Ki
for CYP2C8 inhibition is 0.4–63 mM (Mancy et al., 1996;Hamman et al., 1997).2. Natural Compounds. A range of natural com-
pounds have been tested for CYP2C8 inhibition in vitro,and inhibition parameters have been determined forseveral of them (Table 7). In a CYP inhibition screeningof 10 herbal products commercially available in Aus-tralia, horsetail (Equisetum arvense) affected CYP2C8with an IC50 of 93.0 mg/ml (Sevior et al., 2010). Theauthors suggested that the inhibition of CYP2C8 byhorsetail, which is used for treatment of urinary tractinfections, cystitis, and prostate problems, may beclinically relevant (Sevior et al., 2010). In another invitro study, six herbal supplements inhibited CYP2C8to various degree, but the inhibition by cranberrypowder (IC50 = 24.7 mg/ml) and saw palmetto (IC50 =15.4 mg/ml) were suggested to potentially be of clinicalsignificance (Albassam et al., 2015).Among five CYP enzymes tested, CYP2C8 was most
sensitive to inhibition by green tea extract in HLM(IC50 = 4.5mg/ml) (Misaka et al., 2013). Themajor catechinin green tea, (2)-epigallocatechin-3-gallate, inhibitedCYP2C8 with a Ki of 6.8 mM, indicating that green teaintake may affect CYP2C8 in vivo. It has been reportedthat 15% of Japanese older than 40 years of ageconsume more than 1.8 l of green tea daily, correspond-ing to a daily epigallocatechin-3-gallate intake of 540–720 mg (Misaka et al., 2013).
B. Metabolism-dependent Inhibition
Metabolism-dependent inhibitors are compoundsthat are metabolized to metabolites or reactive inter-mediates that cause time-dependent enzyme inhibition.Metabolism-dependent inhibition may be either direct,quasi-irreversible, or irreversible (mechanism-basedinhibition). Mechanism-based inhibitors inactivatetheir victim enzymes permanently, and enzyme activitycan only be regained by de novo synthesis of theenzyme (Lin and Lu, 1998). Interestingly, two glucuro-nide metabolites, gemfibrozil 1-O-b glucuronide andclopidogrel acyl 1-b-D-glucuronide, affect CYP2C8 by
mechanism-based inhibition or quasi-irreversible in-hibition, leading to clinically important drug-druginteractions (Figs. 2 and 5; Table 8; Ogilvie et al.,2006; Tornio et al., 2014). Very recently, also the acylglucuronide of deleobuvir, an HCV protease inhibitor,was found to be a very potent mechanism-based in-hibitor of CYP2C8 (Sane et al. 2015). In addition, thereis in vitro evidence suggesting that the carbamoylglucuronide metabolite of Lu AA34893 may affectCYP2C8 in a similar manner (Kazmi et al., 2010). Ofinterest, parent clopidogrel and gemfibrozil do not seemto be metabolized by CYP2C8. For example, clopidogrelis mainly eliminated by carboxylesterase 1, whereas itsactivation is dependent on CYP2C19 and CYP3A4(Mega et al., 2009; Simon et al., 2009; Holmberg et al.,2014; Tarkiainen et al., 2015).
The inhibitory effect of gemfibrozil on CYP2C8 isbased principally on its metabolite, gemfibrozil 1-O-bglucuronide, which is formed mainly by UGT2B7 inhepatocytes (Shitara et al., 2004; Ogilvie et al., 2006;Mano et al., 2007). Themetabolite acts as amechanism-based inhibitor of CYP2C8, with inhibitor concentra-tion supporting half of the maximal rate of enzymeinactivation (KI) and maximal rate of inactivation (kinact)values of 20–52 mM and 0.21 1/min in vitro (Ogilvieet al., 2006; Baer et al., 2009). Similarly, clopidogrel acyl1-b-D-glucuronide causes a metabolism-dependent in-hibition of CYP2C8 with KI and kinact values of 9.9 mMand 0.047 1/min (Tornio et al., 2014). The in vivoconsequences of the inhibitory effects of these metabo-lites are discussed in section VI. In an in vitro studyby Jenkins et al. (2011), the acyl glucuronides of ator-vastatin, dehydroketoprofen, diclofenac, ibuprofen,indomethacin, rac-ketoprofen, mefenamic acid, R- andS-naproxen, and simvastatin did not affect CYP2C8 bymetabolism-dependent inhibition.
Several other metabolism-dependent inhibitors ofCYP2C8 have been reported in the literature (Table 8).However, the clinical importance of their interactionpotential is unknown.
C. Induction
Increased expression of CYP2C8 protein in hepato-cytes due to enzyme-inducing drugs/xenobiotics is animportant mechanism of drug-drug interactions thatcan lead to markedly increased clearance of CYP2C8substrates, resulting in reduced efficacy and therapeu-tic failure. Several drug-responsive nuclear receptors,including CAR, PXR, VDR, and GR, can mediate thetranscriptional activation of the CYP2C8 gene byrecognizing the respective responsive elements withinthe 59-flanking promoter region of the gene (Chen andGoldstein, 2009). After activation of nuclear receptorsby their ligands/activators (in particular, enzyme in-ducing drugs), the nuclear receptors enter the nu-cleus, bind to their responsive elements in the DNA,recruit coactivators that affect chromatin structure,
210 Backman et al.
TABLE
8Metab
olism-dep
ende
ntCYP2C
8inhibitors
invitro
Inhibitor
Therap
euticUse
and/or
Dru
gClass
Mod
eof
Inhibition
Preinc.
IC50a
IC50Shiftb
KI
k inact
Test
System
Marke
rRea
ctionc
Referen
ces
mM
ratio
mM
1/min
17a-E
thinylestrad
iol
Con
tracep
tive
,hormon
ede
riva
tive
8.3
1.9
HLM
Pacli
Cha
nget
al.,20
09Amioda
rone
Antiarrh
ythmic
1.5
0.07
9rC
YP2C
8Pacli
Polas
eket
al.,20
0451
.20.02
9HLM
Pacli
Polas
eket
al.,20
04Bosutinib
Anticanc
er,PKI
16.9
2.6
54.8
0.01
8HLM
Amo
Filpp
ulaet
al.,20
14Clopido
grel
acyl
1-b-D
-glucu
ronide
Dru
gmetab
olite
12.0
4.7
9.9
0.04
7HLM
Amo
Tornioet
al.,20
14
Desethy
lamioda
rone
Dru
gmetab
olite
0.67
3.3
4.4
0.00
9HLM
Amo
Oba
chet
al.,20
07Dem
ethylda
brafen
ibDru
gmetab
olite
30a
1.6
HLM
Rosi
Law
renc
eet
al.,20
14Fluox
etine
Antidep
ressan
t,SSRI
Qua
si-irrev
ersible
294
0.08
3rC
YP2C
8Pacli
Polas
eket
al.,20
04Gem
fibrozil1-O-b
gluc
uron
ide
Dru
gmetab
olite
Irreve
rsible
1.8
13.3
20-52
0.21
HLM
Pacli
Ogilvie
etal.,20
06
4.51
0.10
6Hep
n/a
Neg
ishi
etal.,20
0729
0.07
2rC
YP2C
8Amo
Bae
ret
al.,20
090.46
98HLM
Amo
Perloffet
al.,20
093.0
HLM
Mon
teKaron
enet
al.,20
104.5
HLM
Mon
te-4
Karon
enet
al.,20
100.26
0.01
5HLM
Amo
Ten
get
al.,20
101.4
16HLM
Amo
Jenk
inset
al.,20
1110
.10.04
1HLM
Amo
Van
denB
rink
etal.,20
1121
.30.05
0HLM
Mon
teVan
denB
rink
etal.,20
1135
0.02
2HLM
Pacli
Van
denB
rink
etal.,20
1133
.60.08
2HLM
Pio
Van
denB
rink
etal.,20
1118
.40.03
5HLM
Rep
aVan
denB
rink
etal.,20
1148
.50.07
1HLM
Rosi
Van
denB
rink
etal.,20
1110
.34–
25.4
0.10
4–0.25
HLM
Amo
Korzekw
aet
al.,20
14Gem
fibrozild 6-1-O
-bglucu
ronide
Dru
gmetab
olite,
Deu
terated
290.03
3rC
YP2C
8Amo
Bae
ret
al.,20
09
Ison
iazid
Antitube
rculosis
Qua
si-irrev
ersible
374
0.04
2rC
YP2C
8Pacli
Polas
eket
al.,20
0417
00.01
2HLM
Pacli
Polas
eket
al.,20
04LuAA34
893carbam
oyl
glucu
ronide
Dru
gMetab
olite
8.5
8.4
HLM
n/a
Kaz
miet
al.,20
10
O-m
ethy
lgem
fibrozil
acyl-b- D-glucu
ronide
Gem
fibrozilAcyl-b-D-glucu
ronideAna
log
173.2
HLM
Amo
Jenk
inset
al.,20
11
Nortriptyline
Antidep
ressan
t,TCA
Qua
si-irrev
ersible
49.9
0.03
6rC
YP2C
8Pacli
Polas
eket
al.,20
04Phen
elzine
Antide
pressa
nt,MAOI
1.2
0.24
3rC
YP2C
8Pacli
Polas
eket
al.,20
0454
.30.17
HLM
Pacli
Polas
eket
al.,20
04Ralox
ifen
eAntiosteope
rotic,
SERM
.2
0.26
0.1
rCYP2C
8Pacli
Van
denB
rink
etal.,20
12Thu
jops
ene
Sesqu
iterpe
ne29
.83.3
HLM
Amo
Jeon
get
al.,20
14Torem
ifen
eAntican
cer,
SERM
5.0
1.9
HLM
Pacli
Kim
etal.,20
11b
Verap
amil
Antihyp
ertens
ive,
CCB
Qua
si-irrev
ersible
17.5
0.06
5rC
YP2C
8Pacli
Polas
eket
al.,20
04
CCB,calcium
chan
nel
blocke
r;Hep
,hep
atocytes:H
LM,h
uman
live
rmicrosomes;I
C50,inhibitor
concentrationsu
pporting
halfof
themax
imal
inhibition;K
I,inactiva
tion
constan
t;k i
nact,m
axim
alrate
ofinactiva
tion
;MAOI,
mon
oamineox
idas
einhibitor;n/a,not
available;
PKI,
protein
kinas
einhibitor;rC
YP2C
8,recombina
ntCYP2C
8,SERM,selectiveestrog
enreceptor
mod
ulator;
SSRI,
selectiveserotonin
reuptak
einhibitor;TCA,tricyclic
antide
pressa
nt.
aPreinc.
IC50de
pictsIC
50afterpr
eincu
bation
ofinhibitor
for30
min
withNADPH
before
addition
ofsu
bstrate,
except
inthecase
ofde
methylda
brafen
ibwherethepr
eincu
bation
timewas
20min.
bIC
50sh
ift=reve
rsible
IC50/preinc.
IC50.A
nIC
50sh
ift$1.5-fold
isindicative
ofmetab
olism-dep
ende
ntinhibition.
c Amo,
amod
iaqu
ineN-dee
thylation;M
onte,m
onteluka
st36
-hyd
roxy
lation
;Mon
te-4,formationof
mon
teluka
stM4;
Pacli,p
aclitaxe
l6a-hyd
roxy
lation
;Pio;p
ioglitaz
onehyd
roxy
lation
(M-IV);Rep
a,repa
glinide39-hyd
roxy
lation
;Rosi,rosiglitaz
oneN-dem
ethylation.
Role of CYP2C8 in Drug Metabolism and Interactions 211
and increase the transcription of the target genes(Handschin and Meyer, 2003). Apart from this generalmechanism, certain compounds, such as phenobarbitaland CITCO ([6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime),seem to cause induction by increasing the nucleartranslocation of CAR, which is constitutively active(Zelko et al., 2001). Other nuclear receptors and tran-scriptional factors, such as HNF4a, HNF3g, C/EBPa,and RORs, can regulate the constitutive expression ofCYP2C genes, but these factors are probably not di-rectly involved in induction of CYP2C8 (Ferguson et al.,2005; Chen and Goldstein, 2009; Rana et al., 2010). Yet,at leastHNF4a seems to be required for upregulation bythe PXR agonist rifampin (Rana et al., 2010).In experimental in vitro studies, several compounds
and ligands of the different nuclear receptors have beenable to induce CYP2C8 (Table 9). On the basis of studiesin cultured human hepatocytes, CYP2C8 is the mostinducible member of the CYP2C subfamily (Gerbal-Chaloin et al., 2001; Feidt et al., 2010). Regardinginducibility of CYP2C8, the PXR-receptor seems to bethe most important nuclear receptor, because typicalPXR ligands/activators strongly induce CYP2C8 in vitro(Ferguson et al., 2005; Chen and Goldstein, 2009) andcan cause induction of CYP2C8 also in vivo, whereasligands of the other nuclear receptors cause only moder-ate induction of CYP2C8 in vitro (Ferguson et al., 2005;Chen and Goldstein, 2009) and have not been shown tomarkedly induce CYP enzymes in vivo in humans. PXRactivators, such as phenobarbital, hyperforin (an in-gredient of St. John’swort), and rifampin, have increasedCYP2C8 expression at mRNA, protein, and activitylevels several-fold in vitro (Dussault et al., 2001;Gerbal-Chaloin et al., 2001; Rae et al., 2001; Nishimuraet al., 2002; Raucy et al., 2002; Madan et al., 2003;Ferguson et al., 2005; Komoroski et al., 2005; Thomaset al., 2015). In addition, certain other compounds,including ritonavir, nelfinavir, cyclophosphamide, lith-ocholic acid, and paclitaxel can induce CYP2C8 pre-sumably by a PXR-mediatedmechanism in vitro (Changet al., 1997; Dussault et al., 2001; Synold et al., 2001;Ferguson et al., 2005; Dixit et al., 2007). It should benoted that in one study, rifampin induced CYP2C8mRNA in only three of the eight commercially availablecryopreserved hepatocyte lots tested (Yajima et al.,2014), suggesting that cryopreserved hepatocytes maynot be a reliable system for studying CYP2C8 induction.Apart from PXR, induction of CYP2C8 can be exper-
imentally achieved at least via CAR- and GR-mediatedand possibly also via VDR- and PPAR-alpha-mediatedmechanisms (Ferguson et al., 2005; Chen and Goldstein,2009). The CAR-agonists phenytoin and CITCO havemarkedly induced CYP2C8 expression in human hepa-tocytes (Ferguson et al., 2005). In addition, dexameth-asone (GR agonist) can modestly increase CYP2C8expression in in vitro systems (Gerbal-Chaloin et al.,
2001; Rae et al., 2001; Raucy et al., 2002; Madan et al.,2003; Ferguson et al., 2005). Moreover, VDR maybe involved in the induction of CYP2C8 by lithocholicacid in HepG2 cells (Makishima et al., 2002; Yajimaet al., 2014), and the PPAR-alpha-agonist WY14,643(4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid)has induced CYP2C8 mRNA in HepaRG cells (Thomaset al., 2015). In addition to the above compounds,certain other drugs have weakly induced CYP2C8 invitro with unknown induction mechanisms, includingtasimelteon and crizotinib (FDA, 2011e,m; EMA, 2012c;TGA, 2014).
In humans in vivo, rifampin has markedly reducedthe plasma exposure to several CYP2C8 substrates(Jaakkola et al., 2006a; Niemi et al., 2000; Niemiet al., 2004a; Park et al., 2004), and it is consequentlythe preferred CYP2C8 inducer drug for use in clinicalstudies (section VII). Yet, the strength of the CYP2C8inducing effect of rifampin (or any other PXR ligands)has been difficult to estimate, because the strongCYP3A4-inducing effect of rifampin is likely to partiallyexplain its effects on the clearance of CYP2C8 sub-strates. Of note, one of the strongest clinical inducers ofCYP enzymes, carbamazepine, which is also a weakPXR activator, seems to be poorly characterized withregard to CYP2C8 both in vitro and in vivo.
VI. Clinical Drug Interactions Mediated viaCytochrome P450 2C8
A. General Aspects
The CYP2C8 enzyme is involved in many drug-druginteractions in humans, including interactions basedon either inhibition or induction of CYP2C8. However,its exact role in interactions is difficult to determine,because there are no fully selective in vivo inhibitorsor inducers of CYP2C8 and all known CYP2C8 sub-strates aremetabolized, at least to a small degree, also byother enzymes. Furthermore, the activities of OATP1B1,P-glycoprotein or other membrane transporters canaffect the pharmacokinetics of many CYP2C8 substratedrugs, and some inhibitors of CYP2C8 inhibit thesetransporters, too. Because drug metabolizing enzymesand transporters may influence drug metabolism inconcert, the isolated role of CYP2C8 in many drug-druginteractions can be very difficult to dissect in vivo.
The clinical significance of pharmacokinetic drug-drug interactions depends both on the therapeutic indexof victim drug and on the extent of pharmacokineticchanges, in addition to various patient-related clinicalfactors. Of the pharmacokinetic parameters, at least theplasma AUC, peak concentration (Cmax), time to max-imum concentration (tmax), and elimination half-life (t1/2)values are generally required for the characterizationof an interaction. Here, to be brief, we usually reportonly fold-changes of the mean AUC values causedby interactions. Of note, e.g., interindividual genetic
212 Backman et al.
TABLE 9Some inducers of CYP2C8 in vitro
Inducer Therapeutic Useand/or Drug Class CYP2C8 mRNA CYP2C8 Protein in
HepatocytesCYP2C8 Activityin Hepatocytes References
CITCO 2.5-fold in primary hepatocytes Ferguson et al., 20051-fold in primary hepatocytes Thomas et al., 2015
Clofibric acid Antihyperlipidemic 2-to 3-fold in primaryhepatocytes
Prueksaritanontet al., 2005
Cyclophosphamide Anticancer, alkylating agent + Chang et al., 1997Dexamethasone Anti-inflammatory,
glucucortidcoid+ Chang et al., 1997
3-fold in primary hepatocytes 2-fold Gerbal-Chaloinet al., 2001
5-fold in primary hepatocytes 4-fold Raucy et al., 2002,2-fold in primary hepatocytes Ferguson et al., 2005
Fenofibric acid Antihyperlipidemic 2- to 6-fold in primaryhepatocytes
Prueksaritanontet al., 2005
Gemfibrozil Antihyperlipidemic,PPARa agonist
1.1- to 5-fold in primaryhepatocytes
Prueksaritanontet al., 2005
Hyperforin Constituent of St. John’swort
+ in primary hepatocytes Dussault et al., 2001
5-fold in primary hepatocytes Ferguson et al., 2005+ Komoroski et al., 2005
Idelalisib Anticancer, PKI 3.9-fold in human hepatocytes FDA, 2014hIdelalisib metabolite
GS-563117Drug metabolite 1.4-fold in human hepatocytes FDA, 2014h
Ifosfamide Anticancer, alkylating agent + Chang et al., 1997Lithocholic acid Bile acid ,2-fold in primary hepatocytes Ferguson et al., 2005Nelfinavir Antiviral, protease inhibitor 5-fold in primary hepatocytes 2-fold Dixit et al., 2007Nilotinib Anticancer, PKI No induction of CYP2C8
mRNA.2-fold FDA, 2007c
Paclitaxel Anticancer, taxane 4-fold in primary hepatocytes Ferguson et al., 2005+ in primary hepatocytes Synold et al., 2001
Phenobarbital Antiepileptic, barbiturate + Chang et al., 19973-fold in primary hepatocytes 3-fold Gerbal-Chaloin
et al., 20017-fold in primary hepatocytes Raucy et al., 2002
3- to 6-fold Madan et al., 20032-fold in primary hepatocytes Ferguson et al., 2005
Phenytoin Antiepileptic 2-fold in primary hepatocytes Ferguson et al., 2005Progesterone Hormonal replacement
therapy1.4- to 9.2-fold in primary
hepatocytesChoi et al., 2013
Rifampin(rifampicin)
Antibiotic + Chang et al., 1997
6-fold in primary hepatocytes 3-fold Gerbal-Chaloinet al., 2001
6.5-fold in primary hepatocytes Rae et al., 2001+ in primary hepatocytes Dussault et al., 2001+ in primary hepatocytes Synold et al., 20017- to 12-fold in primary
hepatocytes6-fold (1- to 17-fold) Raucy et al., 2002
4- to 8-fold in primaryhepatocytes
Madan et al., 2003
3-fold in primary hepatocytes 3- to 10-fold Ferguson et al., 20054- to 9-fold in primary
hepatocytesPrueksaritanont
et al., 20057-fold in primary hepatocytes 4-fold Dixit et al., 20076.5-fold in primary hepatocytes Rana et al., 20100.7- to 3-old in primary
hepatocytesYajima et al., 2014
5-fold in HepaRG cells Thomas et al., 2015Ritonavir Antiviral, protease inhibitor + in primary hepatocytes Dussault et al., 2001
+ in primary hepatocytes Synold et al., 20017-fold in primary hepatocytes 2-fold Dixit et al., 2007
SR12813 Antihyperlipidemic,HMG-CoAreductase inhibitor
+ in primary hepatocytes Synold et al., 2001
Tasimelteon Circadian regulator 4.4-fold FDA, 2014mWY14,643 Antihyperlipidemic,PPARa
agonist4-fold in HepaRG cells Thomas et al., 2015
CITCO, [6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; PKI, proteinkinase inhibitor, HepaRG, hepatocyte-like cells from the human hepatoma HepaRG cell line; mRNA, messenger RNA; PPAR, peroxisome proliferator-activated receptor;SR12813, tetraethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethenyl-1,1-bisphosphonate; WY14,643, 4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid.
Role of CYP2C8 in Drug Metabolism and Interactions 213
variation in the activity of drug metabolizing enzymesand transporters can cause a considerable variability inthe extent of drug interactions. In particular, it isimportant to note that in an individual patient theexposure to a victim drug can change much more thanthe generally reported mean change.Recognition of the role of CYP2C8 as an important
oxidative enzyme in drugmetabolismhas led to changes inproduct information of many drugs, resulting in betterpredictability of their interactions and improved safety. Insome cases, CYP2C8-mediated drug interactions and theresultant adverse effects have forced the manufacturersto withdraw drugs from clinical use or to add contraindi-cations or limitations to their use. In general, specialattention is needed, if a drug with narrow safety margin isextensivelymetabolized by CYP2C8 or if a drug is a strongCYP2C8 inhibitor like gemfibrozil and clopidogrel. Inaddition, it should be recognized that rifampin and someotherpotent enzyme inducers canmarkedly reduceplasmaconcentrations and effects of CYP2C8 substrate drugs.As gemfibrozil is a well-characterized inhibitor of
CYP2C8 that has increased the plasma concentrationsof several drugs (Fig. 7; Table 10), we first present adetailed description of it as an in vivo inhibitor in thefollowing part. The other clinically relevant CYP2C8inhibitors, including clopidogrel, trimethoprim, efavirenz,and teriflunomide (Niemi et al., 2004b; Germanet al., 2007; FDA, 2012a; Tornio et al., 2014), are dealtwith in the next part, where we focus on the CYP2C8-inhibition-mediated drug interactions of differenttherapeutic CYP2C8 substrate drugs. Thereafter, wepresent CYP2C8 induction-mediated drug interactionsand their clinical relevance.
B. Gemfibrozil as Prototypical Inhibitor
1. In Vitro Versus In Vivo. In vitro, the parentgemfibrozil is a moderately potent competitive inhibitorof CYP2C9 (Ki value of 5.8 mM;Wen et al., 2001), but it isover 10 times less potent as inhibitor of CYP2C8 (Ki valueof 75 mM, Wang et al., 2002; Ki 87 mM, Prueksaritanontet al., 2002; Table 6). Gemfibrozil in concentrations up to1,000 mM has no effect on CYP3A4 activity (midazolam19-hydroxylation) (Backman et al., 2000), but it is ratherpotent as an inhibitor of theOATP1B1 transporter, with aKi value ranging in different studies from 4 to 31.7 mM(Schneck et al., 2004; Yamazaki et al., 2005; Hirano et al.,2006; Nakagomi-Hagihara et al., 2007).
In healthy volunteers, gemfibrozil (600 mg twice daily)slightly (by 23%) increased the AUC of a CYP2C9substrate drug glimepiride (Niemi et al., 2001) but didnot increase the exposure to racemic warfarin (Liljaet al., 2005). Gemfibrozil even caused a small butstatistically significant decrease (211%) in the AUC ofthe CYP2C9 substrate S-warfarin. These results stronglysuggest that gemfibrozil is not a meaningful inhibitorof CYP2C9 in vivo in humans.
In vivo gemfibrozil is glucuronidated by the UGT 2B7enzyme to gemfibrozil 1-O-b-glucuronide. The benzylicoxidation of the glucuronide by CYP2C8 leads to haemalkylation and irreversible inactivation of CYP2C8(Baer et al., 2009; Jenkins et al., 2011). In HLM, thekinact value of CYP2C8 by gemfibrozil 1-O-b-glucuronidehas been 0.21 1/min and KI 20–52 mM (Ogilvie et al.,2006). The glucuronide metabolite is also a competitiveinhibitor of OATP1B1 (OATP2) transporter (Ki 24 mM;Shitara et al., 2004). On the basis of clinical studies on
Fig. 7. Effects of gemfibrozil on the exposure (area under the plasma drug concentration-time curve) to different CYP2C8 substrate drugs. The effect ofgemfibrozil on drug exposures may also include inhibition of OATP1B1 (cerivastatin acid, lovastatin acid, paritaprevir, repaglinide, and simvastatinacid). Dasabuvir and paritaprevir were administered as a dasabuvir-paritaprevir-ritonavir combination. A fold increase of 1 refers to no effect ofgemfibrozil on drug exposure. References are given in Table 10.
214 Backman et al.
TABLE 10Drug-drug interactions caused by CYP2C8-inhibiting drugs in humans
Inhibitor Dosing Substrate AUC Change References
foldAtazanavir 400 mg once daily for 6 days, substrate on day 6 Rosiglitazone 1.4 FDA, 2015bClopidogrel 75–300 mg for 3 days, substrate on days 1 and 3 Repaglinide 3.9–5.1a Tornio et al., 2014Deferasirox 30 mg/kg once daily for 3 days, substrate on day 4 Repaglinide 2.3b Skerjanec et al., 2010Efavirenz 400 mg once daily for 12 days, substrate on day 9 Amodiaquine 1.8 Soyinka et al., 2013
Active metabolite:N-desethylamodiaquine
0.7 Soyinka et al., 2013
Enzalutamide 160 mg once daily for 97 days, substrate on day 42 Pioglitazone n.s. (1.2) Gibbons et al., 2015Active metabolite:hydroxypioglitazone (M-IV)
0.63 Gibbons et al., 2015
Gemfibrozil 600 mg twice daily for 6 days, substrate on day 6 Alogliptin 1.1b FDA, 2013gActive metabolite: M-I 1.9b FDA, 2013g
600 mg twice daily for 7 days, substrate on day 4 Brivaracetam 1.0 Nicolas et al., 2012600 mg twice daily for 3 days, substrate on day 3 Cerivastatin (acid) 5.6a Backman et al., 2002
Cerivastatin lactone 4.4 Backman et al., 2002600 mg twice daily for 4 days, substrate on day 4 Dabrafenib 1.5 Suttle et al., 2015600 mg twice daily for 5 days, substrate on day 4 Daprodustat (GSK1278863A) 18.6 Johnson et al., 2014600 mg twice daily for 5 days, substrate on day 3 Dasabuvir (ABT-333)b 11.3 Menon et al., 2015
Active metabolite:dasabuvir M1
0.22 Menon et al., 2015
600 mg twice daily for 21 days, substrate on day 4 Enzalutamide 4.3 Gibbons et al., 2015Active metabolite:N-demethylenzalutamide
0.75 Gibbons et al., 2015
600 mg twice daily for 7 days, substrate for 7 days Ezetimibe 1.4b Reyderman et al., 2004600 mg twice daily for 3 days, substrate on day 3 R-Ibuprofen 1.3 Tornio et al., 2007600 mg twice daily for 6 days, substrate on day 3 Imatinib n.s. Filppula et al., 2013b
Active metabolite:N-demethylimatinib
0.5 Filppula et al., 2013b
600 mg twice daily for 5 days, substrate on day 3 Loperamide 2.2 Niemi et al., 2006600 mg twice daily for 3 days, substrate on day 3 Montelukast 4.6 Karonen et al., 2010
Active metabolite: 36-hydroxymontelukast (M6)
0.6c Karonen et al., 2010
Montelukast 4.3 Karonen et al., 2011Active metabolite: 36-hydroxymontelukast (M6
0.6c Karonen et al., 2011
600 mg twice daily for 5 days, substrate on day 3 Paritaprevir (ABT-450)d 1.4a Menon et al., 2015600 mg twice daily for 3 days, substrate on day 3 Pioglitazone 3.4 Deng et al., 2005
Active metabolite:hydroxypioglitazone (M-IV)
n.s. Deng et al., 2005
Active metabolite:ketopioglitazone (M-III)
n.s. Deng et al., 2005
600 mg twice daily for 4 days, substrate on day 3 Pioglitazone 3.2 Jaakkola et al., 2005Active metabolite:ketopioglitazone (M-III)
0.6 Jaakkola et al., 2005
Active metabolite:hydroxypioglitazone (M-IV)
0.6 Jaakkola et al., 2005
600 mg twice daily for 4 days, substrate on day 3 Pioglitazone 4.3 Aquilante et al., 2013a600 mg twice daily for 3 days, substrate on day 3 Repaglinide 8.1a Niemi et al., 2003b600 mg twice daily for 3 days, substrate on day 3 7.3-8.3a Kalliokoski et al., 2008b600 mg twice daily for 3 days, substrate on day 3 7.0a Tornio et al., 2008a600 mg twice daily for 3 days, substrate on days 3-6 1.0-7.6a Backman et al., 2009A single dose of 30-900 mg 1 h prior to substrate
intake1.8-8.3a Honkalammi et al., 2011a
A single dose of 600 mg 0-6 h prior to substrateintake
5.0-6.6a Honkalammi et al., 2011b
30–600 mg twice daily for 5 days, substrate on day 5 3.4-7.0a Honkalammi et al., 2012600 mg twice daily for 4 days, substrate on day 3 Rosiglitazone 2.3 Niemi et al., 2003a600 mg twice daily for 3 days, substrate on day 3 Simvastatin (lactone) 1.4 Backman et al., 2000
Simvastatin acid 2.9a Backman et al., 2000600 mg twice daily for 3 days, substrate on day 4 Sitagliptin 1.5e Arun et al., 2012600 mg twice daily for 4 days, substrate on day 3 Treprostinil 1.9 FDA, 2009b600 mg twice daily for 8 days, substrate on day 3 R-Warfarin 0.9 Lilja et al., 2005.
S-Warfarin 0.9 Lilja et al., 2005.600 mg twice daily for 3 days, substrate on day 3 Zopiclone n.s. Tornio et al., 2006
N-demethylzopiclone 1.2 Tornio et al., 2006N-oxide-zopiclone 2.0 Tornio et al., 2006
Teriflunomidef 14–70 mg once daily for 12 days, substrateon day 12
Repaglinide 2.3a FDA, 2012a
Trimethoprim 960 mg (combination)g twice daily for 6 days,substrate on day 6
Amodiaquine 1.6 Akande et al., 2015
Active metabolite:N-desethylamodiaquine
0.9 Akande et al., 2015
160 mg twice daily for 3 days, substrate on day 3 Cerivastatin (acid) 1.4 Backman et al., 2003Cerivastatin lactone 1.5 Backman et al., 2003
(continued )
Role of CYP2C8 in Drug Metabolism and Interactions 215
the dose/time dependency of the effect of gemfibrozil onthe pharmacokinetics of repaglinide and statisticalmodels of enzyme and transporter inhibition, it hasbeen estimated that the in vitro mechanism-basedinhibition of CYP2C8 by gemfibrozil 1-O-b-glucuronidemanifests into a strong and long-lasting inhibitionof CYP2C8 at typical clinical doses of gemfibrozil(Backman et al., 2009; Honkalammi et al., 2011a,b). Inaddition, the OATP1B1 inhibitory effect of the glucuro-nide can lead to an up to ;50% transient inhibition ofOATP1B1 in vivo. These effects are the main explana-tion to the effects of gemfibrozil on CYP2C8 andOATP1B1 substrates (Honkalammi et al., 2012). Sim-ilar estimations have been obtained with physiologi-cally based pharmacokinetic modeling in a recentpublication (Varma et al., 2015).2. Gemfibrozil Dose Versus CYP2C8 Inhibition.
Single oral doses of gemfibrozil, i.e., 30, 100, 300, or 900mg ingested 1 hour before repaglinide, increased theAUC of repaglinide in a dose-dependent manner 1.8-,4.5-, 6.7-, and 8.3-fold compared with placebo, respectively(Fig. 8; Honkalammi et al., 2011a). Also after multipledoses of gemfibrozil (30, 100, or 600 mg twice daily for5 days), the exposure to repaglinide increased dosedependently, but the greatest AUC increase did notexceed that observed after the single 900 mg gemfibrozildose (Honkalammi et al., 2012). Thus, the maximuminhibition of CYP2C8 can be achieved by a single 900-mgdose of gemfibrozil (Fig. 9). Gemfibrozil in doses of 100mg twice daily at steady state causes an about 95%inhibition of CYP2C8 (Fig. 9), and in doses of 10mg twicedaily, it causes an about 50% inhibition (Honkalammiet al., 2011a). The fraction of a small 0.25-mg dose ofrepaglinide metabolized by CYP2C8 is about 80–90%.However, because repaglinide is metabolized to someextent also by CYP3A4, the relative role of CYP2C8 andCYP3A4 in the biotransformation of repaglinide candepend on its dose and plasma concentrations as wellas on individual pharmacogenetic factors (Bidstrup et al.,2003; Kajosaari et al., 2005a; Säll et al., 2012).3. Onset and Duration of CYP2C8 Inhibition by
Gemfibrozil. The onset and duration of CYP2C8
inhibition by gemfibrozil have been studied in healthyvolunteers using the gemfibrozil-repaglinide interac-tion as a model. Single 600-mg doses of gemfibrozilingested 0, 1, 3, or 6 hours before repaglinide (0.25 mg)increased the geometric mean AUC of repaglinide 5.0-,6.3-, 6.6-, and 5.4-fold, respectively (Fig. 8). The Cmax ofthe CYP2C8-mediated repaglinide M4-metabolite was1.0-, 0.10-, 0.06-, and 0.09-fold compared with controlphase, respectively (Honkalammi et al., 2011b). Theseresults indicate that the strong inactivation of CYP2C8occurs rapidly, being evident alreadywithin 1 hour afteroral dosing of gemfibrozil.
When repaglinide was ingested 1, 24, 48, or 96 hoursafter discontinuation of a gemfibrozil treatment (600 mgtwice daily for 3 days), the AUC of repaglinide was7.6-, 2.9-, 1.4-, and 1.0-fold compared with the controlphase, respectively (Backman et al., 2009). Thesefindings confirmed and extended the previous findings,which had shown that the inhibitory effect of gemfibro-zil persists for at least 12 hours after its ingestion(Tornio et al., 2008a). As the half-lives of gemfibroziland its glucuronide are very short (about 1–2 hours),these findings convincingly demonstrate that the effectof gemfibrozil on repaglinide pharmacokinetics is basedon irreversible mechanism-based inhibition of CYP2C8.A several-fold increase in repaglinide AUC was evidenteven at very low plasma concentrations of gemfibrozil1-O-b-glucuronide, which are less than 1% of its peakconcentrations. The results also showed that fullCYP2C8 activity recovers gradually within 3–4 daysafter cessation of the clinically used therapeutic doses of600 mg twice daily gemfibrozil.
4. Quantification of CYP2C8-Mediated Drug Interac-tions in Humans. Interactions caused by a combina-tion of two or more drugs, which inhibit, in addition toCYP2C8, also some other crucial enzyme or transporter,can increase exposure to a CYP2C8 substrates muchmore than is the sum of their separate effects causing aclassic potentiation phenomenon. Thus, e.g., exposureto repaglinide is increased only slightly by itraconazolealone (1.4-fold), greatly by gemfibrozil alone (8.1-fold),and drastically (19.4-fold) by their combination (Fig. 10;
TABLE 10—Continued
Inhibitor Dosing Substrate AUC Change References
960 mg (combination)g twice daily for 3 days, substrateon day 2
Loperamide 1.9 Kamali and Huang, 1996
160 mg twice daily for 6 days, substrate on day 3 Pioglitazone 1.4 Tornio et al., 2008bActive metabolite:hydroxypioglitazone (M-IV)
1.1 Tornio et al., 2008b
160 mg twice daily for 3 days, substrate on day 3 Repaglinide 1.6 Niemi et al., 2004b160 mg twice daily for 4 days, substrate on day 3 Rosiglitazone 1.4 Niemi et al., 2004a200 mg twice daily for 5 days, substrate on day 5 1.3 Hruska et al., 2005
AUC, area under the plasma concentration-time curve; n.s. not statistically significant.aInhibition of OATP1B1 may also be involved.bThe role of CYP2C8 in the interaction is limited or unclear.cAUC0–7 hour.dGiven as a dasabuvir-paritaprevir-ritonavir combination.eInhibition of OAT3 may also be involved.fOf note, teriflunomide is the active metabolite of leflunomide. Hence, coadministration of leflunomide with CYP2C8 substrate drugs may also cause interactions.gTrimethoprim was given in a combination with sulfaphenazole (cotrimoxazole).
216 Backman et al.
Niemi et al., 2003b). The quantitative rationalization ofgemfibrozil-drug interactions and consideration oftransporter-enzyme interplay have been dealt quiterecently by Varma et al. (2015).
C. Inhibition-Mediated Drug Interactions and TheirClinical Significance
1. Repaglinide. Interactions of the oral antidiabeticdrug repaglinide have been studied extensively, and itis a recommended model substrate drug for CYP2C8 in-teraction studies (EMA, 2012b; http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm). In healthyvolunteers, gemfibrozil (600 mg twice daily for 3 days)raised the AUC of repaglinide 8.1-fold, itraconazoleraised it 1.4-fold, and their combination raised it19.4-fold (Niemi et al., 2003b). Gemfibrozil alone andin combination with itraconazole considerably enhanced
also the blood glucose lowering effect of repaglinide(Niemi et al., 2003b). This pioneering study clearlyindicated that the extent of interaction caused by acombination of two drugs can greatly exceed the sum oftheir separate effects. On the basis of these results andclinical observations of serious hypoglycemic episodesin diabetic patients, The European Agency for theEvaluation of Medicinal Products gave “EMEA publicstatement on repaglinide contraindication of concomi-tant use of repaglinide and gemfibrozil” (21.05.2003).Also the U.S. Food and Drug Administration warnedagainst repaglinide-gemfibrozil interaction. The effectof gemfibrozil on repaglinide exposure was laterconfirmed and characterized in several studies as de-scribed in previous paragraphs (sections VI.B.1–3). Thegemfibrozil-repaglinide interaction is mainly mediatedvia inhibition of CYP2C8 and OATP1B1 by the gemfi-brozil 1-O-b-glucuronide.
Fig. 8. Effects of gemfibrozil on the exposure (area under the plasma drug concentration-time curve) to repaglinide (Repa) and its metabolites M1, M2,and M4. Fold changes in drug exposure compared with the control phase when repaglinide was taken 1 hour after a single 30-, 100-, 300-, or 900-mgdose of gemfibrozil (A) or 1 hour after the last dose of 30, 100, or 600 mg gemfibrozil twice daily (B). Fold changes in drug exposure as compared with thecontrol phase, when a single 600-mg dose of gemfibrozil was taken simultaneously or 1, 3, or 6 hours before repaglinide intake (C) or when the last doseof gemfibrozil was taken 0, 1, 3, 6, 12, 24, 48, or 96 hours before repaglinide intake (D). For M4, AUC0-3 hour data are presented. For all othercompounds, AUC0-‘ data are presented. A fold change of 1 refers to no effect of gemfibrozil on exposure. References are given in the text.
Role of CYP2C8 in Drug Metabolism and Interactions 217
The antimicrobial drug trimethoprim (160 mg twicedaily for 3 days) raised in healthy volunteers the AUC ofrepaglinide by 1.6-fold compared with placebo (Niemiet al., 2004b). Symptomatic hypoglycemia developed ina diabetic patient 5 days after addition of trimethoprim/sulfamethoxazole therapy to his previously well-toleratedrepaglinide (1 mg three times daily) treatment (Roustitet al., 2010).The 300-mg loading dose of clopidogrel raised the
AUC of repaglinide by 5.1-fold, and the following daily75-mg doses of clopidogrel raised the AUC by 3.9-foldin healthy volunteers (Tornio et al., 2014). The increasein repaglinide AUC caused by clopidogrel was highest insubjects with the CYP2C8*1/*4 genotype (Tornio et al.,2014). The clopidogrel-repaglinide interaction is medi-ated by formation of the clopidogrel acyl-b-D-glucuronide,which is a potent time-dependent inhibitor of CYP2C8.On the basis of this short-term study, it has beenextrapolated that the daily treatment with 75 mg ofclopidogrel causes a continuous, 60–85% inhibition ofhepatic CYP2C8 under steady-state conditions duringchronic clopidogrel use. The pharmacokinetic interactionof clopidogrel and repaglinide resulted in an enhancedblood glucose-lowering effect of repaglinide. The con-comitant use of repaglinide and clopidogrel is now
contraindicated, e.g., in Canada (http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2015/54454a-eng.php).
The immunosuppressant teriflunomide (70 mg oncedaily for 4 days, followed by 14 mg once daily for 8 days)increased the AUC of repaglinide by 2.3-fold in healthymale subjects (FDA, 2012a) compared with whenrepaglinide was given alone. In three subjects theAUC was raised by 3.2- to 3.6-fold. Teriflunomideinhibits both CYP2C8 and OATP1B1, and the contri-bution of each mechanism to the increase in repaglinideexposure has not been established (FDA, 2012a). Ofnote, teriflunomide is the active metabolite of lefluno-mide and its plasma concentrations following lefluno-mide administration are equal to those observed whenit is given alone. Hence, leflunomide may also be aclinically relevant CYP2C8 inhibitor.
Care is warranted if inhibitors of CYP2C8 arecombined with repaglinide. In particular, combinationof strong CYP2C8 inhibitors, such as gemfibrozil andclopidogrel, with repaglinide should be avoided. Bloodglucose levels and symptoms of hypoglycemia should bemonitored closely and the doses modified as needed.The interactions with repaglinide are likely to bestronger in CYP2C8*3 carriers than in CYP2C8*1homozygotes (Tornio et al., 2008a).
2. Other Oral Antidiabetic Drugs. The Europeanproduct information of Actos (pioglitazone) stated ear-lier (e.g. 2004) that metabolism of pioglitazone occurspredominantly via CYP3A4 and CYP2C9 (Jaakkolaet al., 2005), whereas the U.S. label stated that the majorCYP isoforms involved were CYP2C8 and CYP3A4(FDA, 1999). The in vitro study of Jaakkola et al.(2006c) showed that pioglitazone is metabolized mainly
Fig. 10. Effects of gemfibrozil (Gem), itraconazole (Itra), or theircombination (Gem + itra) on the exposure (area under the plasma drugconcentration-time curve) to repaglinide, loperamide, montelukast, andpioglitazone. A fold increase of 1 refers to no effect of inhibitors on drugexposure. References are given in Table 10 and in the text.
Fig. 9. Predicted effects of different gemfibrozil doses on CYP2C8-mediated drug metabolism. Predicted fold increase in the AUC0–‘ of adrug metabolized by CYP2C8, when the fraction of the substrate drugmetabolized by CYP2C8 (fm,CYP2C8) varies between 50 and 99% (A),and the CYP2C8 activity remaining (B) after a gemfibrozil dose rangingfrom 0 to 600 mg twice daily in steady-state conditions. Modified fromHonkalammi et al. (2012). AUC, area under the concentration-time curve.
218 Backman et al.
by CYP2C8 and to lesser extent by CYP3A4, whereasCYP2C9 is not significantly involved in pioglitazoneelimination. In healthy volunteers, gemfibrozil raisedthe mean AUC of pioglitazone 3.2-fold (range 2.3-foldto 6.5-fold) and its elimination half-life 2.7-fold, butitraconazole had no effect on pioglitazone and did notalter the effect of gemfibrozil on its pharmacokinetics(Jaakkola et al., 2005). In two other studies, gemfibrozilincreased the mean AUC of pioglitazone 3.4-fold (Denget al., 2005) and 4.3-fold (range 1.3-fold to 12.1-fold)(Aquilante et al., 2013a). CYP2C8 genotype influencesthe relative change in pioglitazone exposure aftergemfibrozil administration. Thus, CYP2C8*3 carriershad a greater mean increase by gemfibrozil in pioglita-zone AUC (5.2-fold) compared with CYP2C8*1 homozy-gotes (3.3-fold) (Aquilante et al., 2013a). Trimethoprim(160 mg twice daily) raised in healthy volunteers theAUC of pioglitazone by 1.4-fold and had opposite effectson pioglitazone pharmacokinetics compared with theeffects of CYP2C8*3 allele during the placebo phase(Tornio et al., 2008b).The AUC of rosiglitazone was raised in healthy
volunteers by gemfibrozil by 2.3-fold (Niemi et al.,2003a). In another study, trimethoprim (160 mg twicedaily) increased rosiglitazone AUC by 1.4-fold and re-duced the formation ofN-demethylrosiglitazone (Niemiet al., 2004a). The effect of trimethoprim (200 mg twicedaily) on rosiglitazone pharmacokinetics was confirmedby Hruska et al. (2005), who also demonstrated thecompetitive inhibition of rosiglitazone p-hydroxylationby trimethoprim in vitro. Atazanavir (400 mg once daily)increased the AUC of a single dose of rosiglitazone by1.4-fold (FDA, 2015b).The AUC of nateglinide was increased only by 1.5-fold
by 3 days’ pretreatment with therapeutic doses of bothgemfibrozil and itraconazole (Niemi et al., 2005a). Thus,neither CYP2C8 nor CYP3A4 has a substantial signif-icance to the pharmacokinetics of nateglinide. Gem-fibrozil increased also the AUC of the dipeptidylpeptidase inhibitor sitagliptin by 1.5-fold (Arun et al.,2012). However, the gemfibrozil-sitagliptin interactionseems to be mainly mediated by inhibition of the renalOAT3, with a minor contribution by CYP2C8.If gemfibrozil, clopidogrel, or other inhibitors of
CYP2C8 will be combined with pioglitazone or rosiglita-zone, blood glucose levels, symptoms of hypoglycemia, andother potential adverse effects (e.g., fluid retention) shouldbe monitored closely and the doses be modified as needed.As shown for the gemfibrozil-pioglitazone and gemfibrozil-repaglinide interactions (Tornio et al., 2008a; Aquilanteet al., 2013a), interactions may be stronger in CYP2C8*3carriers than in CYP2C8*1 homozygotes.3. Amodiaquine. Although amodiaquineN-deethylation
is a widely used marker reaction for CYP2C8 activityin vitro, the sensitivity of amodiaquine to CYP2C8inhibition is poorly characterized in humans. Amodia-quine is rapidly and extensively metabolized by
CYP2C8 to active desethylamodiaquine, which has along half-life of 9–18 days. In healthy subjects, tri-methoprim and efavirenz have been reported to in-crease the AUC of amodiaquine by 1.6- and 1.8-fold,respectively, and to reduce that of desethylamodiaquineby 12 and 26%, respectively (Soyinka et al., 2013;Akande et al., 2015). In an earlier study, efavirenzraised the AUC of amodiaquine in two healthy subjectsby 2- to 4-fold and decreased the AUC of desethylamo-diaquine by 24 and 8.5% (German et al., 2007). In both ofthese subjects, marked elevation of hepatic transami-nase levels occurred several weeks after stopping the 3days’ combined use, forcing premature discontinuationof the interaction study. The dramatic, delayed hepato-toxicity warrants great care in combination of anyCYP2C8 inhibitor with amodiaquine.
4. Statins. Cerivastatin was initially considered as asafe statin because of its dual biotransformation routes,mediated both via CYP3A4 and CYP2C8 (Mück, 1998;2000). However, it soon became obvious that cerivasta-tin greatly increased the incidence of fatal rhabdomyol-ysis, particularly when taken along with gemfibrozil(Staffa et al., 2002). Consequently, cerivastatin waswithdrawn from the market in 2001, only 3 years afterits launch. Despite the “dual metabolic pathway” andsupposed "low propensity for drug interactions" (Mücket al., 1998; Mück, 2000), the elimination of cerivastatinrelied predominantly on CYP2C8. In healthy volun-teers, gemfibrozil (600 mg twice daily) raised the AUCof the parent cerivastatin (acid) by 5.6-fold, the AUCof cerivastatin lactone by 4.4-fold, and that of theCYP3A4-dependent metabolite M-1 by 4.35-fold,whereas gemfibrozil decreased the AUC of theCYP2C8-dependent metabolite M-23 by 78% (Fig. 11;Backman et al., 2002). The increased exposure tocerivastatin, to its lactone, and to M-1 and the reducedformation of the CYP2C8-dependent metabolite re-vealed the strong CYP2C8 inhibitory effect of gemfi-brozil. In addition to irreversible inhibition of CYP2C8by gemfibrozil 1-O-b-glucuronide, inhibition of thehepatic OATP1B1 may contribute to the gemfibrozil-cerivastatin interaction (Ogilvie et al., 2006; Shitaraet al., 2004; Tamraz et al., 2013).
Interestingly, about 10 years after the withdrawal ofcerivastatin, it was found that in addition to gemfibro-zil, also concomitant use of clopidogrel was stronglyassociated with cerivastatin-induced rhabdomyolysis,with an odds ratio of ;30 (48 when gemfibrozil userswere excluded) (Floyd et al., 2012). Recently, Tornioet al. (2014) showed that glucuronidation convertsclopidogrel to a strong time-dependent inhibitor ofCYP2C8, clopidogrel acyl-b-D-glucuronide. The forma-tion of this metabolite leads to uninterrupted inhibitionof CYP2C8 during clopidogrel treatment and explainsthe increased risk of rhabdomyolysis during concomi-tant use of cerivastatin and clopidogrel (Tornio et al.,2014). Also trimethoprim increased the AUC of
Role of CYP2C8 in Drug Metabolism and Interactions 219
cerivastatin (by 1.4-fold) and its lactone (1.5-fold)(Backman et al., 2003). Because cerivastatin has beenwithdrawn from the market, its interactions are nomore of direct clinical relevance. However, they areexamples of clinically important challenges in drugdevelopment and have been of paramount importancein understanding the significance of CYP2C8 in drugmetabolism.Interestingly, cerivastatin and repaglinide have
pharmacokinetic similarities. Both drugs are sub-strates of CYP2C8, CYP3A4, and OATP1B1. TheCYP3A4 inhibitor itraconazole has raised their AUConly slightly, i.e., by 1.4-fold (repaglinide), 1.15-fold(cerivastatin acid), and 1.8-fold (cerivastatin lactone),whereas gemfibrozil has raised their AUC values muchmore, i.e., by 8.1-fold (repaglinide), by 5.6-fold (cerivas-tatin), and by 4.4-fold (cerivastatin lactone) (Kantolaet al., 1999; Backman et al., 2002; Niemi et al., 2003b).Because the combination of a CYP3A4 inhibitor and aCYP2C8 inhibitor caused a drastic increase in repagli-nide AUC (by 19.4-fold; Niemi et al., 2003b), it isreasonable to assume that also the exposure to cerivas-tatin acid and to its more lipophilic lactone form haveraised even more by gemfibrozil—or clopidogrel—if thepatients had been using also CYP3A4 inhibiting drugs.However, there seems to be no studies on the effect ofCYP2C8 and CYP3A4 inhibitor combinations on theplasma concentrations of cerivastatin.
Gemfibrozil raises the AUC of nearly all statin acids,including simvastatin acid, lovastatin acid, atorva-statin, pravastatin, rosuvastatin, and pitavastatin(Neuvonen et al., 2006). However, the role of CYP2C8 insome gemfibrozil-statin interactions seems to be limited ornonexistent. They are mainly mediated by inhibitionof OATP1B1, OAT3, or other transporters (Shitaraet al., 2004; Neuvonen, 2010; Niemi et al., 2011).
5. Anticancer Drugs. Most anticancer drugs have anarrow therapeutic range. Although paclitaxel is a well-established CYP2C8 probe in vitro, its interactions withCYP2C8 inhibitors and inducers have not been widelystudied in humans. Lapatinib and pazopanib are rela-tively strong inhibitors of CYP2C8, and they haveraised the AUC of paclitaxel up to 1.8-fold (Tan et al.,2014). In a case report, the only clopidogrel user in acohort of 93 ovarian carcinoma patients treated withpaclitaxel had the second lowest clearance of unboundpaclitaxel in the cohort. She was hospitalized threetimes because of severe paclitaxel toxicity (Bergmannet al., 2015).
Gemfibrozil has raised the AUC of the androgenreceptor antagonist enzalutamide by 4.3-fold, and itra-conazole raised it by 1.4-fold compared with control(Gibbons et al., 2015). These results agree well with the invitro findings that CYP2C8 is the predominant enzyme inthe elimination of enzalutamide. The composite exposureof enzalutamide and its active metabolite was raised by
Fig. 11. Effects of gemfibrozil on the plasma concentrations of cerivastatin, its lactone, and M-1 and M-23 metabolites after administration ofcerivastatin 0.3 mg with gemfibrozil 600 mg or placebo twice daily for 3 days (modified from Backman et al., 2002).
220 Backman et al.
2.2-fold by gemfibrozil and by 1.3-fold by itraconazole. Areduction of the enzalutamide dose by about 50% isrecommended when gemfibrozil is used concomitantly.There are no published studies on the effect of clopidogrelon enzalutamide pharmacokinetics. However, a closefollow up and reduction of enzalutamide dose can berecommended also in their possible coadministration. Itshould also be noted that combined inhibition ofCYP2C8 and CYP3A4 can cause a greater increase inenzalutamide + metabolite AUC. Enzalutamide itself isan inhibitor of CYP2C8 and may moderately raise theexposure to its substrate drugs, e.g., pioglitazone AUCby 20% (Gibbons et al., 2015).Gemfibrozil did not affect the AUC of imatinib
after a single imatinib dose but reduced the AUC ofN-demethylimatinib by 48%, indicating a significantparticipation of CYP2C8 in themetabolism of imatinib inhumans (Filppula et al., 2013b). After a single dose,imatinib seems to be mainly metabolized by CYP3A4,but the fraction of imatinib metabolized by CYP3A4decreases after its multiple doses because of auto-inhibition of the CYP3A4-mediated metabolism ofimatinib (Filppula et al., 2012, 2013a). This autoinhibi-tion is likely to increase the relative role of CYP2C8in imatinib elimination and its sensitivity to interac-tions caused by CYP2C8 inhibitors during long-termtreatment. According to pharmacokinetic simulations,imatinib exposure may raise up to twofold at steady stateif a strong CYP2C8 inhibitor is given concomitantly withimatinib (Filppula et al., 2013b).In melanoma patients, gemfibrozil increased the
AUC of the CYP3A4 and CYP2C8 substrate dabrafenibby 1.5-fold and ketoconazole increased it by 1.7-fold(Suttle et al., 2015). It is probable that a combinedadministration of CYP2C8 inhibitors and CYP3A4inhibitors with dabrafenib can increase its exposuremore than does either of these inhibitors alone. Inaddition to paclitaxel, dabrafenib, and imatinib, someother anticancer drugs are metabolized by CYP2C8(Table 1). However, their interactions with CYP2C8inhibitors have not been characterized in humans.Considering the narrow therapeutic range of manyanticancer drugs, close follow up for possible adverseeffects is warranted if gemfibrozil, clopidogrel, trimeth-oprim, or other inhibitors of CYP2C8 are used with pacli-taxel or other anticancer drugs metabolized by CYP2C8.6. Antiviral Drugs. Gemfibrozil (600 mg twice daily)
has increased the AUC of the antihepatitis C drugdasabuvir about 11-fold and their concomitant use iscontraindicated (Menon et al., 2015). It is reasonable toassume that also other potent inhibitors of CYP2C8such as clopidogrel increase greatly the exposure todasabuvir, and their use together should be avoided orthe dose of dasabuvir be reduced markedly. It can bespeculated that savings could be achieved by usingsmall amounts of expensive dasabuvir (about one-tenthof normal dose) with small doses (e.g., 100 mg) of
gemfibrozil. This should lead to similar plasma concen-trations of dasabuvir as those achieved by normaldasabuvir doses administered without inhibitor ofCYP2C8. Also some other new antiviral drugs arepartially metabolized by CYP2C8, but their suscepti-bility to interact with drugs affecting CYP2C8 activityin humans needs further studies.
7. Antiasthmatic Drugs. In healthy volunteers.gemfibrozil raised the AUC of montelukast 4.5-foldand its elimination half-life 3.0-fold (Karonen et al.,2010). Gemfibrozil reduced the AUC of the secondaryM4 metabolite of montelukast by more than 90%. Inanother study, gemfibrozil alone raised the AUC ofmontelukast 4.3-fold, itraconazole had no significanteffects, and the effects of the gemfibrozil-itraconazolecombination on montelukast pharmacokinetics did notdiffer from those of gemfibrozil alone (Karonen et al., 2012).These findings indicate that CYP2C8 but not CYP3A4 isimportant in the pharmacokinetics of montelukast. Incontrast to the effect of gemfibrozil on montelukast, thepharmacokinetics of zafirlukast is not affected by gemfi-brozil (Karonen et al., 2011), although both of thesecysteinyl leukotriene receptor antagonists are potent invitro inhibitors of CYP2C8 (Walsky et al., 2005a).
Montelukast has a relatively large safety margin, andthe clinical significance of its interactions with CYP2C8inhibitors seems to be limited. However, neuropsychi-atric symptoms have developed in a woman with HIVinfection when montelukast was added to her therapycontaining the CYP2C8 inhibitor efavirenz (Ibarra-Barrueta et al., 2014). She had used efavirenz, emtrici-tabine, and tenofovir disoproxil fumarate for yearswith good tolerance until montelukast was startedfor asthma. Shortly thereafter unbearable symptomsappeared, consisting of disturbed sleep, vivid dreamsand irritability, confusion, and concentration difficulties.After 2 months of concomitant use, montelukast waswithdrawn and the psychiatric symptoms completely dis-appeared. This case report indicates that adverse effectscan develop when these drugs are used together, althoughthe mechanism of adverse effects is not fully clear.
8. Other Substrate or Inhibitor Drugs. Gemfibrozilraised in healthy volunteers the AUC of loperamide2.1-fold, itraconazole raised it 3.8-fold, and thegemfibrozil-itraconazole combination raised lopera-mide AUC 12.6-fold compared with placebo phase(Niemi et al., 2006). This finding strongly suggeststhat gemfibrozil can markedly increase the loperamideexposure in subjects who are using potent inhibitorsof CYP3A4, i.e., when another important metabolicroute is blocked. Administration of cotrimoxazole(trimethoprim + sulphamethoxazole) has increased theAUC of loperamide by 1.9-fold (Kamali and Huang,1996). Also some other opioids, e.g., buprenorphine, areCYP2C8 substrates (Table 1). However, there seem to beno published studies on their possible interaction withgemfibrozil or other CYP2C8 inhibitors.
Role of CYP2C8 in Drug Metabolism and Interactions 221
Gemfibrozil raised the AUC of the prolyl hydroxylaseinhibitor agent daprodustat (GSK1278863) 18.6-fold(Johnson et al., 2014). This result together with in vitrostudies indicates the crucial significance of CYP2C8 inits pharmacokinetics. CYP2C8 inhibitors should not beused with this erythropoiesis-stimulant agent or its doseneeds to be reduced very greatly. On the other hand, atleast theoretically, it could be possible to take advantage ofthis interaction in a product containing very small doses ofdaprodustat and gemfibrozil.In healthy volunteers, gemfibrozil raised only slightly
the AUC of R-ibuprofen, by 1.3-fold, after the ingestionof racemic ibuprofen (Tornio et al., 2007). In vitroCYP2C8 participates in the metabolism of zopiclone(Becquemont et al., 1999). In humans, however, gemfi-brozil did not increase the AUC of the parent zopiclonebut moderately (2-fold and 1.2-fold) increased the AUCof its potentially active metabolites (Tornio et al., 2006).Also many other drugs are substrates of CYP2C8 invitro, but their concomitant administration with gemfi-brozil hasnot appreciably increased theirAUC, suggestingthat the CYP2C8-mediated biotransformation is of lim-ited significance to their total clearance (Table 1).Many compounds are moderate inhibitors of CYP2C8
in vitro, but their concomitant ingestion with repagli-nide or other CYP2C8 substrates does not raise expo-sure to these substrates in humans. The reason for theapparent discrepancy between the in vitro and in vivoresults can be, for example, their low potency asCYP2C8 inhibitors or their high protein binding in vivo(e.g., montelukast).Some parent drugs such as gemfibrozil and clopidog-
rel are relatively weak inhibitors of CYP2C8 in vitro,but they are metabolized in vivo to glucuronide metab-olites, which are potent CYP2C8 inhibitors. In general,negative interaction results with gemfibrozil in vivoexclude a clinically meaningful interaction mediatedby CYP2C8 inhibition. On the other hand, increasedexposure to a victim drug by gemfibrozil does not yetindicate that CYP2C8 has a significant role in itsmetabolism because there may be other mechanismsmediating the observed interaction.Patients often concomitantly use different drugs
that together inhibit several CYP enzymes, e.g.,CYP1A2, CYP2C8, CYP2C9, CYP2B6, CYP2D6, orCYP3A4. The combined inhibition of two or more ofthese enzymes often results in patients in a strongerinteraction than is caused by inhibition of a singleenzyme in healthy volunteer studies. This aspecttogether with other causes of interindividual variationshould be taken into consideration when the results ofexperimental interaction studies in healthy volunteersare translated into the clinic.
D. Induction-Mediated Drug Interactions
Rifampin (rifampicin) can markedly increase theclearance of many CYP2C8 substrate drugs, decrease
their AUC, and diminish their clinical efficacy. BothCYP2C8 and CYP3A4 are involved in the biotransfor-mation of many drugs, which can also be substrates ofvarious transporters (Table 1). Because both CYP2C8 andCYP3A4 enzymes and some transporters can be highlyinducible, the importance of CYP2C8 in many rifampininteractions is difficult to determine exactly (Niemi et al.,2000). Apart from rifampin, there are very few clinicalstudies concerning the effects of other CYP enzymeinducers on the pharmacokinetics of CYP2C8 substrates.
1. Rifampin (Rifampicin). Rifampin (600 mg/day),given for several days, has decreased the plasmaexposure to repaglinide by 31–80% depending on thetime interval from the last rifampin dose to repaglinideingestion (Table 11; Niemi et al., 2000; Hatorp et al.,2003; Bidstrup et al., 2004). The time interval affectsthe extent of interaction because rifampin is alsoa competitive inhibitor of OATP1B1, CYP2C8 andCYP3A4 (Kajosaari et al., 2005a; Varma et al., 2013).Interestingly, intake of St John’s Wort for 14 days hashad no significant effect of the pharmacokinetics ofrepaglinide (Fan et al., 2011).
Rifampin has also reduced the concentrations of thethiazolidinediones pioglitazone and rosiglitazone. Ri-fampin caused a substantial (54%) decrease in the AUCof pioglitazone and increased the ratios of metaboliteM-IV to pioglitazone and of M-III to pioglitazone in urineby 98 and 95% (Jaakkola et al., 2006a). Similarly,rifampin reduced the mean AUC of rosiglitazone by54% and increased the formation of N-demethylrosigli-tazone (Niemi et al., 2004a). In Korean men, rifampindecreased rosiglitazone AUC by 65% (Park et al., 2004).Addition of tuberculosis treatment, containing rifam-pin, to treatment of a woman with type 2 diabetescaused her to lose glycemic control, demonstrating poten-tial clinical significance of the rifampin-rosiglitazoneinteraction (Pimazoni, 2009).
VII. Points to Consider When InvestigatingCytochrome P450 2C8-Mediated Drug
Metabolism and Interactions
Studies focusing on drug metabolism and metabolicdrug-drug interactions are an essential part of moderndrug development, from early preclinical phases tothe clinical development phase and beyond. By usingspecific and sensitive research methods, it is possibleto get a detailed and accurate view of potential issuesrelated to variability in drugmetabolism already duringthe preclinical and early clinical phases of development.Methods to investigate CYP2C8 in vitro and in clinicalstudies have evolved markedly even during the lastdecade.
A. In Vitro
1. General Aspects. Comprehensive in vitro studiesto investigate the roles of different CYP enzymes in the
222 Backman et al.
metabolism of a (new) drug and to uncover its potentialfor causing inhibition or induction of drug metabolismare typically conducted already during the early pre-clinical phases of drug development. The results fromthese studies are then used for in vitro-in vivo extra-polations, to anticipate factors affecting the clearanceof the drug as well as its potential to act as a perpetratorof pharmacokinetic drug interactions, i.e., to affect theclearance of other drugs. The prerequisite for accurateextrapolations is that in vitro investigations are con-ducted with care and are sufficiently comprehensive,avoiding the many pitfalls of in vitro studies, under-standing the many limitations of the different ap-proaches, and covering complex issues, such as thepotential for autoinhibition or -induction. Yet it shouldbe understood that accurate extrapolations are notpossible without some clinical pharmacokinetic dataat the relevant dose of the investigational drug.The general aspects as well as the potential pitfalls of
in vitro studies and extrapolations are well covered bymanyexcellent review articles and guidelines (Houston andGaletin, 2008; Pelkonen et al., 2008; Grimm et al., 2009;EMA, 2012b; Pelkonen, 2015; http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm). Therefore,this review focuses on issues that are directly relatedto CYP2C8, i.e., in vitro methods used for measurementof CYP2C8 activity (e.g., to test the potential of theinvestigational drug to inhibit CYP2C8 activity) andreaction phenotyping (does CYP2C8 metabolize thedrug) and in vivo studies to characterize the druginteraction potential of the new drug (either as aperpetrator or victim drug).2. Assessment of CYP2C8 Activity In Vitro.
Specific assessment of CYP2C8 activity is necessary, inparticular when studying the potential of a drug to causeinhibition of CYP2C8 but alsowhenusing a panel ofHLMfor reaction phenotyping using the correlation approach.An ideal in vitro probe substrate is selective/specific, hasa sufficient turnover, follows Michaelis-Menten kinetics,and is not sensitive to experimental conditions. There areseveral useful, selective probe substrates to studyCYP2C8 in vitro, including paclitaxel, amodiaquine,
montelukast, rosiglitazone, pioglitazone, and cerivasta-tin, each having its specific strengths and weaknesses(Tables 12 and 13).
Paclitaxel 6-a-hydroxylation is the prototypicalmarker reaction for CYP2C8 (Rahman et al., 1994;Sonnichsen et al., 1995). It is highly selective forCYP2C8, but the metabolic turnover is fairly low, oftenleading to relatively long incubation times, which maylead to significant inhibitor metabolism/depletion dur-ing the incubation (Table 13). This may partly explainwhy paclitaxel seems to be less sensitive to competitiveCYP2C8 inhibitors than most other CYP2C8 markersubstrates (VandenBrink et al., 2011). In particular,long incubation times should be avoided when studyingthe potential for time-dependent or mechanism-basedinhibition in systems based on a preincubation step,because inactivation proceeding during the incubationmay decrease the sensitivity of the experimental systemto detect inactivation.
Amodiaquine metabolism to N-desethylamodiaquineis probably the second most used CYP2C8 markerreaction. It is well characterized and highly selectivefor CYP2C8 and has a high turnover (Li et al., 2002),allowing for short incubation times. Overall, it seems tohave no major drawbacks in in vitro use.
Few years ago, montelukast, a selective competitiveinhibitor of CYP2C8, was shown to be a potentialCYP2C8 marker substrate, because its 36-hydroxylation(M6 formation) is mediated primarily by CYP2C8 witha minor contribution by CYP2C9 (Filppula et al., 2011).In a successive study, montelukast 36-hydroxylationproved to be a sensitive and useful reaction to in-vestigate CYP2C8 inhibition in vitro (VandenBrinket al., 2011). One of the weaknesses of montelukastis that it is highly susceptible to microsomal proteinbinding, necessitating careful standardization of incuba-tion conditions (Walsky et al., 2005b).
Of the other potential marker reactions, cerivastatin6-hydroxylation (M-23 formation) seems to be highlyspecific for CYP2C8 (Wang et al., 2002; Shitara et al.,2004). In addition, the hydroxylations of rosiglitazone(p-hydroxylation) (Baldwin et al., 1999) and pioglita-zone (M-IV formation; Jaakkola et al., 2006c) seem to be
TABLE 11Drug-drug interactions caused by the CYP2C8-inducing drug rifampin (rifampicin) in humans
Inducer DosingTime Interval from the
Previous Rifampin Dose toSubstrate Ingestion
Substrate AUC Decrease References
hours %
600 mg once daily for 6 days 13 Pioglitazone 54 Jaakkola et al., 2006a- Active metabolite: ketopioglitazone (M-III) 39 Jaakkola et al., 2006a- Active metabolite: hydroxypioglitazone (M-IV) 34 Jaakkola et al., 2006a
600 mg once daily for 5 days 12.5 Repaglinide 57 Niemi et al., 2000600 mg once daily for 7 days 1 31 Hatorp et al., 2003600 mg once daily for 7 days 0 48 Bidstrup et al., 2004
24 80 Bidstrup et al., 2004600 mg once daily for 5 days 13 Rosiglitazone 54 Niemi et al., 2004a600 mg once daily for 6 days 12 65 Park et al., 2004
AUC, area under the plasma concentration-time curve.
Role of CYP2C8 in Drug Metabolism and Interactions 223
relatively, albeit not completely, selective for CYP2C8.Finally, the most used in vivo CYP2C8 probe drugrepaglinide, although sometimes recommended as an invitro probe (Kajosaari et al., 2005a; VandenBrink et al.,2011), is challenging to use in vitro, e.g., because of aneed for extremely low substrate concentrations andlack of commercially available metabolite standards(Table 13).3. In Vitro Methods to Estimate the Contribution
of CYP2C8 in the Metabolism of a Drug. The basicmethods used for estimating the contributions of CYPenzymes to the metabolism of a drug, i.e., the so-calledreaction phenotyping, are the use of diagnostic inhibi-tors in a complete natural system, such asHLM, and theuse of recombinant expressed enzymes. In both ap-proaches, knowledge of clinically relevant concentra-tions of the drug is a prerequisite for estimation of thecontributions of the different CYP enzymes in vivo. Theadvantage of HLM is the natural composition of thesystem, allowing relatively straightforward estimationof the contributions. However, this approach requireshuman material collected according to high ethicalstandards and is entirely dependent on the strengthand specificity of the inhibitors. On the other hand,although recombinant expressed enzymes can beregarded as a specific tool, in vivo extrapolations ofrecombinant enzyme results require the use of en-zyme source and batch specific conversion factors(preferably based on enzyme activity), complicatingthe extrapolations.Recombinant expressed human CYP2C8 is commer-
cially available at least as bacterial cell- and insect cell-based products. During the last decade, both chemicalinhibitors and inhibitory antibodies have become avail-able that are both CYP2C8 specific and strong. In thefollowing, we review the documentation regardingchemical CYP2C8 inhibitors.
One of the most widely used chemical CYP2C8inhibitors is quercetin (Rahman et al., 1994). However,it is neither very selective for CYP2C8 nor very strongand therefore, it can barely be recommended as adiagnostic inhibitor. Today, there are several moreselective alternatives available, including trimetho-prim, montelukast, and gemfibrozil 1-O-b-glucuronide.
The IC50 of trimethoprim for CYP2C8 is approxi-mately 50 mM, i.e., it is not a very strong inhibitor, butits IC50 for other CYP enzymes is at least one order ofmagnitude greater, making it a relatively selectiveinhibitor (Wen et al., 2002). Montelukast, on the otherhand, is a potent and highly selective competitiveinhibitor of CYP2C8, with an IC50 as low as 0.01 mM,when a low microsomal protein concentration is used,whereas its IC50 for other CYP enzymes is at least twoorders of magnitude greater (Walsky et al., 2005b). Themajor drawback of montelukast seems to be its non-specific microsomal protein binding, whereby increas-ing the microsomal protein concentration by 80-foldyields an about 100-fold decrease in its inhibitionpotency (Walsky et al., 2005b).
Themechanism-basedCYP2C8 inactivator gemfibrozil1-O-b-glucuronide is another appealing CYP2C8 inhibi-tor.With a 30-minute preincubation, its IC50 for CYP2C8is about 2 mM, whereas its IC50 values for CYP1A2,CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 aremore than 300 mM, suggesting an even better selectivitythan that of montelukast (Ogilvie et al., 2006). Moreover,it is unlikely to be markedly affected by microsomalprotein concentration. Whether clopidogrel acyl-b-D-glucuronide is a similarly selective CYP2C8 inactivatorremains to be investigated (Tornio et al., 2014).
B. In Vivo
1. General Aspects. Current guidelines recommendthe conduct of clinical drug-drug interaction studies on
TABLE 12CYP2C8 substrate, inhibitor, and inducer probes recommended for drug-drug interaction studies
Probe EMAa FDAb Helsinki DDI Group
In Vitro In Vivo In Vitro In Vivo In Vitro In Vivo
Substrate Paclitaxel Amodiaquine Paclitaxelc Repaglinide Amodiaquine RepaglinideAmodiaquine Repaglinide Amodiaquine Rosiglitazone Paclitaxel Montelukast
Rosiglitazone Montelukast PioglitazoneCerivastatin (acid) Rosiglitazone(Pioglitazone) (Dasabuvir)
Inhibitor Montelukast Gemfibrozil Montelukastc Gemfibrozil Montelukast GemfibrozilQuercetinc Gemfibrozil
1-O-b glucuronideClopidogrel
Trimethoprim Clopidogrel acyl1-b-D-glucuronide
(Trimethoprim)
Gemfibrozil (Trimethoprim)RosiglitazonePioglitazone
Inducer None recommended None recommended Rifampin (rifampicin) Rifampin (rifampicin) Rifampin (rifampicin) Rifampin(rifampicin)
DDI, drug-drug interaction; EMA, European Medicines Agency; FDA, Food and Drug Administration.aEMA, 2012b.bhttp://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm (Accessed September 15, 2015).cPreferred.
224 Backman et al.
the basis of in vitro studies on the CYP inhibitoryeffects of the drug and its main circulatingmetabolites(potential perpetrator), as well as on the basis of theresults of the in vitro reaction phenotyping studies ofthe drug and its main metabolic pathways (victim). Arational selection for the first CYP-specific clinicalstudies is to focus on the enzyme that is inhibited most(lowest IC50/Ki) by the drug or its metabolite, prefer-ably using the highest clinically used dose of the drug,and on the enzyme that is considered the mostimportant in its own metabolism. For the first typeof studies, a sensitive and selective in vivo probesubstrate is used, and for the second type of studies,a strong and selective in vivo probe inhibitor is needed.For CYP2C8, there are several alternative probesubstrates and a few inhibitors that can be used inclinical trials.
The contribution of CYP2C8 enzyme to the totalclearance of its substrates varies greatly (Table 1).Most CYP2C8 substrates are partially metabolized alsoby other enzymes, are substrates of some membranetransporters, or are excreted in urine or feces in un-changed form. Thus, the significance of CYP2C8 ininteractions cannot be calculated directly from changesin victim drug AUC. If the CYP2C8 substrate drugis also a substrate of transporters or other CYPenzymes, their contribution needs to be considered inthe interaction, as exemplified in the dissection ofthe gemfibrozil-repaglinide interaction (Honkalammiet al., 2011a, 2012). For example, gemfibrozil is in vivoan inhibitor of CYP2C8 as well as of OATP1B1 andOAT3, and it can increase the AUC of certain drugs(e.g., pravastatin), which are not substrates of CYP2C8but are substrates for OATP1B1 or OAT3 (Kyrklundet al., 2003). On the other hand, CYP2C8 inhibitorsusually increase the AUC of CYP2C8 substrates lessthan they diminish the CYP2C8-specific metabolicroutes, because the CYP2C8-independent eliminationroutes remain unaffected.
CYP2C8-mediated drug interactions are often stud-ied in healthy volunteers in a randomized crossovermanner by administering a potential substrate drugwith and without a probe inhibitors of CYP2C8, suchas the recommended probe inhibitor gemfibrozil(Table 12). To better simulate real clinical situationsin which patients often are using several different drugsconcomitantly, substrate drugs can be administered inmultiple-phase studies, given alone, with an inhibitor ofCYP2C8 (gemfibrozil), with an inhibitor of anotherrelevant CYP enzyme (e.g., with CYP3A4 inhibitoritraconazole), and together with a combination ofinhibitors. However, there are only a few studies inwhich the effects of multiple inhibitors (e.g., inhibitorsof CYP2C8 and CYP3A4) on the pharmacokinetics oftheir substrate drugs have been studied both separatelyand together (Niemi et al., 2003b, 2006; Jaakkola et al.,2005; Karonen et al., 2012).
TABLE
13Stren
gths
andwea
knessesof
therecommen
dedpr
obecompo
unds
InVitro
InVivo
Probe
Stren
gths
Wea
knesses
Probe
Stren
gths
Wea
knesses
Subs
trate
Amod
iaqu
ine
Selectivity,high
turn
over
Rep
aglinide
Sen
sitivity,sh
ortha
lf-life
Red
uces
bloodgluc
oseleve
ls,
also
asu
bstrateof
OATP1B
1an
dCYP3A
4Pac
litaxel
Selectivity,ex
tens
ive
docu
men
tation
Low
/interm
ediate
turn
over,
solubility
issu
esMon
teluka
stRelativesens
itivity,
safety
Med
ium
long
half-life
Mon
teluka
stSelectivity
Con
tributionby
CYP2C
9,requ
irem
ent
forve
rylow
subs
trateconc
entration,
issu
eswithpr
oteinbind
ing
Pioglitaz
one
Relativesens
itivity,
safety,no
ta
subs
trateof
OATP1B
1Lon
gha
lf-life
Cerivas
tatin(acid)
Selectivity
Ava
ilab
ilityof
referenc
ecompo
unds
Rep
aglinide
Selectivity
Lackof
metab
olitestan
dard
s,contribu
tion
byCYP3A
4,requ
irem
entforlow
subs
trate
conc
entration
Rosiglitazone
Safety,
not
asu
bstrateof
OATP1B
1Onlymod
eratesens
itivity,
long
half-life,
notea
sily
available
inallcoun
tries
Pioglitaz
one
Selectivity
Low
/interm
ediate
turn
over
Das
abuvir
Sen
sitive
Lackof
docu
men
tation
Rosiglitazone
Selectivity
Low
/interm
ediate
turn
over
Inhibitor
Gem
fibrozil1-O-b
glucu
ronide
Poten
cySelectivity
notwelldo
cumen
ted,
requ
ires
apr
einc
ubation
Gem
fibrozil
Stren
gth,
selectivity
Mod
erateinhibitorof
OATP1B
1an
dOAT3
Clopidog
relac
yl1-b-D
-glucu
ronide
Selectivity
notdo
cumen
ted,
requ
ires
apr
einc
ubation
Clopidog
rel
Stren
gth,
not
aninhibitorof
OATP1B
1or
CYP3A
4AlsoCYP2B
6inhibitor
Mon
teluka
stPoten
cy,selectivity
Alsoasu
bstrateof
CYP2C
8,microsomal
proteinbind
ing
Trimethop
rim
Selectivity
Wea
kinhibitor
Indu
cer
Rifam
pin
(Rifam
picin)
Poten
cy,well-do
cumen
ted
indu
cer
Non
selective
Rifam
pin
(Rifam
picin)
Stron
g,well-do
cumen
tedindu
cer
Non
selective
Role of CYP2C8 in Drug Metabolism and Interactions 225
2. In Vivo Cytochrome P450 2C8 Probe Substrates.The crucial characteristics of an in vivo probe substrateare its selectivity and sensitivity. In an ideal case, atleast 80% of the substrate is metabolized by the enzymeof interest, allowing for an interpretation based on theAUC of the parent drug. In some cases, the use of anenzyme-specific metabolite to parent ratio may beused to increase sensitivity and specificity, but withan additional caveat because of potential variability inmetabolite elimination. The feasibility of an in vivoprobe substrate also depends heavily on its safety, inparticular when large increases in its systemic concen-trations can be anticipated. Moreover, the pharma-cokinetic characteristics of the probe may affect itssuitability. For example, a probe substrate with asignificant first-pass metabolism and short eliminationhalf-life may be able to catch even transient changes inenzyme activity, which may be necessary when study-ing inhibitors with a short half-life or time-dependentchanges in enzyme activity.The antidiabetic agent repaglinide is overall the most
studied and best documented in vivo probe substrate ofCYP2C8, and consequently both the European Medi-cines Agency (EMA) and FDA recommend its use as aCYP2C8 probe (Table 12). Although in vitro studiesare not fully consistent with the major in vivo role ofCYP2C8 in the total metabolism of repaglinide (Ganet al., 2010; Säll et al., 2012; Varma et al., 2013, 2015),repaglinide seems to be very sensitive to inhibitors ofCYP2C8 activity, such as gemfibrozil, trimethoprim,and clopidogrel (Niemi et al., 2003b, 2004b; Tornio et al.,2014). On the basis of detailed mechanistic drug-druginteraction studies with the strong CYP2C8 inactivatorgemfibrozil, it has been estimated that the contributionof CYP2C8 to repaglinide (0.25 mg) metabolism is about85%, indicating that the AUC of repaglinide can beincreased up to an average of sevenfold by strongCYP2C8 inhibition (Honkalammi et al., 2012). Thehalf-life of repaglinide is also relatively short (1 hour),which allows for a full pharmacokinetic study within 1day and can be beneficial when a measure of CYP2C8activity within a narrow time frame is desired. Theweakness of repaglinide is that it is partially metabo-lized by CYP3A4 (Bidstrup et al., 2003; Niemi et al.,2003b; Kajosaari, 2005a) and also a substrate ofOATP1B1 (Niemi et al., 2005b). Thus, e.g., the effect ofgemfibrozil on repaglinide pharmacokinetics is par-tially mediated by inhibition of OATP1B1, in additionto inhibition of CYP2C8 (Honkalammi et al., 2011a).Moreover, as it increases insulin secretion from pancre-atic b cells, there is a risk of hypoglycemia, particularlywhen it is given to healthy subjects. Thus, the smallestpossible dose (e.g., 0.25 mg) of repaglinide should beused, and meals, close follow up, and blood glucosemonitoring be arranged when repaglinide is used.Theoretically, the antimalarial agent amodiaquine and
itsN-deethylation could be useful in vivo CYP2C8 probes.
However, there is very little clinical documentation for itsuse as a probe drug. Moreover, the safety of amodiaquineas an in vivo probe drug in drug-drug interactions studiesseems to be questionable (German et al., 2007).
Of the other potential in vivo probe substrates ofCYP2C8, the two thiazolidinediones pioglitazone androsiglitazone are the best documented. As pointed outin the previous section, CYP2C8 is the main enzymemediating their primary hydroxylation reactions invitro (Baldwin et al., 1999; Jaakkola et al., 2006c).Accordingly, the typical dosing of gemfibrozil 600 mgtwice daily, which has been estimated to cause over 95%inhibition of CYP2C8 (Fig. 9; Honkalammi et al., 2012),increased the AUC of rosiglitazone about 2.3-fold andthat of pioglitazone 3.2-4.3-fold, simultaneously reduc-ing the concentrations of their hydroxyl metabolites(Niemi et al., 2003a; Deng et al., 2005; Jaakkola et al.,2005; Aquilante et al., 2013a). Unlike repaglinide, theyare insensitive to OATP1B1 function (Kalliokoski et al.,2008a). However, they have a long half-life, necessitat-ing an up to 72-hour blood sampling period for a fullpharmacokinetic analysis. On the basis of its betteravailability and sensitivity to CYP2C8 inhibition, pio-glitazone is slightly preferable over rosiglitazone as aCYP2C8 probe.
The leukotriene receptor antagonist montelukast isanother sensitive CYP2C8 substrate that could be usedas a CYP2C8 probe. Gemfibrozil has increased its AUCalmost fivefold and markedly reduced the formation ofits 36-hydroxylated metabolite (Karonen et al., 2010).On the other hand, montelukast is also partiallymetabolized by CYP3A4 in vitro (Filppula et al., 2011;VandenBrink et al., 2011). However, the strongCYP3A4 inhibitor itraconazole has had no effect onmontelukast concentrations (Karonen et al., 2012),indicating that the role of CYP3A4 in montelukastmetabolism is minor. Moreover, montelukast is notknown to be a substrate for OATP1B1.
In addition to the above substrates, there are someother CYP2C8 substrate drugs that could be used as invivo markers on the basis of their sensitivity to interactwith gemfibrozil. Such drugs include, for example,daprodustat and dasabuvir. However, the former isnot yet on the market, and the second one is expensive,and more documentation is needed before they can berecommended as probe substrates.
3. In Vivo Cytochrome P450 2C8 Probe Inhibitors.Probe inhibitors are needed for studying the contri-bution of CYP2C8 in the metabolism of a new drug, aswell as for documenting the risk of drug-drug interac-tions affecting the drug in vivo. Among clinically usedCYP2C8 inhibitors, gemfibrozil is the strongest known.Its CYP2C8 inhibitory effect is also highly selective dueto the specific mechanism that is mediated via specificCYP2C8 inactivation by the glucuronide metabolite ofgemfibrozil (Ogilvie et al., 2006). In vitro, parentgemfibrozil inhibits CYP2C9 activity with a fairly low
226 Backman et al.
Ki (about 6 mM), but its inhibitory effects on the othermain CYP enzymes are much weaker (Backman et al.,2000; Wen et al., 2001; Wang et al., 2002). In clinicalstudies, gemfibrozil at a dose of 600 mg twice daily hasnot increased the concentrations of the CYP2C9 sub-strate warfarin (Lilja et al., 2005) or had any effect thatcould be due to inhibition of CYP3A4 on the concentra-tions of the parent lactone forms of simvastatin andlovastatin (Backman et al., 2000; Kyrklund et al., 2001).On the other hand, gemfibrozil has drastically, up to18.6-fold, increased the AUCs of CYP2C8 substratedrugs (Fig. 7; Table 10), suggesting that with regard toCYP enzymes, the inhibitory effect of gemfibrozil ishighly selective for CYP2C8.The CYP2C8 inhibitory effect of gemfibrozil is strong,
rapid, and long lasting. In studies using repaglinide asthe CYP2C8 probe substrate, subtherapeutic doses ofgemfibrozil have considerably elevated the concentra-tions of repaglinide (Honkalammi et al., 2011a, 2012),and it has been estimated that the clinically usedgemfibrozil dosing (600 mg twice daily) inhibitsCYP2C8 activity by about 99% and that one-tenth ofthis dose would already lead to more than 90% in-hibition of CYP2C8 (Fig. 9). Although CYP2C8 inhi-bition by gemfibrozil is based on time-dependentinactivation of the enzyme by the primary glucuronidemetabolite of gemfibrozil, CYP2C8 inhibition occursrapidly after gemfibrozil dosing. When repaglinidewas given 0, 1, 3, or 6 hours after a single 600 mg doseof gemfibrozil, the AUC of repaglinide was increased5.0-, 6.3-, 6.6-, and 5.4-fold, respectively, indicating thatstrong inhibition of CYP2C8 can be achieved almostimmediately after a single dose of gemfibrozil (Fig. 8,Honkalammi et al., 2011b). It has also been demon-strated that the CYP2C8 inhibitory effect of gemfibrozilpersists virtually unchanged throughout the typical12-hour dosing interval of gemfibrozil (Tornio et al.,2008a). Thus, gemfibrozil can have a strong effect onCYP2C8 substrates, irrespective of their half-life ortime of daily dosing relative to gemfibrozil administra-tion (Fig. 9; Table 10), making it an ideal in vivo probeinhibitor of CYP2C8. The only caveat with gemfibrozil isthat it is also a moderate inhibitor of OATP1B1 andOAT3 and can therefore also increase the concentra-tions of some drugs that are not or only partiallymetabolized by CYP2C8 (Kyrklund et al., 2001, 2003;Backman et al., 2002; Schneck et al., 2004; Neuvonenet al., 2006; Whitfield et al., 2011).Compared with gemfibrozil, all other clinically docu-
mented CYP2C8 inhibitors seem to be suboptimal.Trimethoprim is relatively selective for CYP2C8, butas expected from its in vitro inhibitory effects (Wenet al., 2002), it is only a weak CYP2C8 inhibitor atclinically feasible doses (Niemi et al., 2004a,b; Hruskaet al., 2005; Tornio et al., 2008b), and therefore it canonly be regarded as a confirmatory CYP2C8 inhibitor invivo. Clopidogrel is the second strongest CYP2C8
inhibitor documented so far, increasing the AUC ofrepaglinide about fivefold (Tornio et al., 2014). Clopi-dogrel is obviously also a useful diagnostic CYP2C8inhibitor, but it is not fully selective and has not beenextensively documented so far. In addition to stronglyinhibiting CYP2C8, clopidogrel is also a moderateinhibitor of CYP2B6 (Turpeinen et al., 2005). Further-more, it has been suspected of causing CYP2C19 in-hibition (Nishiya et al., 2009). However, it seems to havepractically no effect on CYP3A4 or OATP1B1 activitiesin vivo (Tornio et al., 2014; Itkonen et al., 2015).
VIII. Conclusions and Future Prospects
CYP2C8 is one of the main oxidative drug metabo-lizing enzymes in the liver. Its expression and functionhave been studied in detail, and for example, it hasbeen estimated that its in vivo turnover half-life isabout 22 hours in humans. The CYP2C8 gene contains9 exons and shares 74% sequence homology withCYP2C9. More than 100 nonsynonymous CYP2C8SNVs are known to date, but only some of them areassociated with functional variability. Interethnicand geographical differences exist in the frequencyof variants. For example, the low-activity variantCYP2C8*2 (c.805A.T) is common in Africans but rarein Caucasians and Asians. CYP2C8*3 (c.416G.A) andCYP2C8*4 (c.792C.G), on the other hand, are com-mon in Caucasians but rare or absent in Africansand Asians (Fig. 6). The interethnic characterizationand functional activity of variants deserve furtherstudies.
Studies on the role of CYP2C8 in drug metabolismhave demonstrated that it is the most importantenzyme for the elimination of several drugs, such ascerivastatin, montelukast, repaglinide, pioglitazone,and rosiglitazone, whose metabolism had been earlierthought to be attributed mainly to other enzymes.CYP2C8 is crucial also for the biotransformation ofdaprodustat (GSK12788693), enzalutamide, dasabuvir,and many other recently developed new drugs, andoverall, it contributes to the elimination of more than100 drugs. CYP2C8 has a large active site cavity, andit can accommodate and also metabolize certain acylglucuronides, such as desloratadine, diclofenac, andsipoglitazar glucuronides.
In vitro, there are several marker reactions for theassessment of CYP2C8 activity, including paclitaxel6-a-hydroxylation, amodiaquine deethylation, montelu-kast 36-hydroxylation, cerivastatin 6-hydroxylation(M-23 formation), rosiglitazone parahydroxylation, andpioglitazone M-IV formation. Each of these reactionshas its strengths and weaknesses. The use of clinicallyrelevant drug concentrations in vitro is a prerequisitefor the estimation of the contribution of differentCYP enzymes in vivo. Gemfibrozil 1-O-b-glucuronideis potent and selective as a diagnostic inhibitor of
Role of CYP2C8 in Drug Metabolism and Interactions 227
CYP2C8-mediated metabolism in vitro. Quercetin andtrimethoprim are relatively weak and unselective asCYP2C8 inhibitors, whereas montelukast is potentand selective, but suffers from nonspecific proteinbinding. Also clopidogrel acyl 1-b-D-glucuronide may bea suitable in vitro inhibitor, but further documentationis needed.Many drugs are CYP2C8 inhibitors or inducers.
Gemfibrozil is in vivo, unlike in vitro, a potent, irre-versible inhibitor of CYP2C8 via formation of gemfi-brozil 1-O-b-glucuronide, and it is widely used as aprobe inhibitor. Also clopidogrel acyl 1-b-D-glucuronidecauses metabolism-dependent inactivation of CYP2C8,indicating that glucuronidesmay contribute as CYP2C8inhibitors to drug-drug interactions. Also efavirenz,trimethoprim, and several protein kinase inhibitorsare inhibitors of CYP2C8.In vivo studies in humans on the role of CYP2C8
are challenged by the lack of suitable selective probesubstrates, inhibitors, and inducers. Although repagli-nide, pioglitazone, rosiglitazone, and montelukast areuseful probe substrates, they all have their pros andcons, as discussed in the text before. With regard toCYP enzymes, gemfibrozil is a selective inhibitor ofCYP2C8 in vivo. Already very small doses of gemfibrozil,i.e., about 10% of its usual therapeutic dose, rapidlycause a strong and long-lasting inactivation of CYP2C8.However, gemfibrozil is also an inhibitor of OATP1B1and OAT3 transporters, which challenges interpreta-tion of the interaction mechanisms if the CYP2C8substrates are also substrates for these transporters.Rifampin is a very unselective albeit strong inducer ofCYP2C8.If a drug is significantly metabolized by CYP2C8 and
CYP3A4, its concomitant administration with inhibi-tors of both of these enzymes, e.g., with gemfibrozil anditraconazole, can cause a much stronger interactionthan is the sum of their separate effects. Thus, the drug-drug interaction studies performed by using inhibitorsof one enzyme only may greatly underestimate thetrue risks as shown by the clinically very importantCYP2C8-mediated interactions affecting repaglinideor cerivastatin. At least theoretically, small doses ofgemfibrozil or other inhibitors of CYPC8 could beused as a booster to optimize the pharmacokineticsof CYP2C8 substrate drugs or to prevent formation ofpotentially toxic metabolites via CYP2C8-mediatedreaction.
Acknowledgments
The authors thank Dr. Tommi Nyrönen for producing the dockingsimulations and three-dimensional artwork in Fig. 2.Backman, Niemi, and Neuvonen have filed a patent application
concerning use of gemfibrozil as a pharmacokinetic enhancer.Some of the information in Tables 1, 3 and 6 is based on the UW
Metabolism and Transport Drug Interaction Database (DIDB),Copyright University of Washington 1999–2015, as specified in thefootnotes to the tables.
Authorship Contributions
Participated in research design: Backman, Filppula, Niemi, andNeuvonen.Wrote or contributed to the writing of the manuscript: Backman,
Filppula, Niemi, and Neuvonen.
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