Emerald MurrellPharmD Candidate 2011
8/27/10
About CYP2B6Located on chromosome 19Makes up about 2-10% of hepatic CYP
contentAlso expressed in brain (significantly higher
in smokers and alcoholics)Metabolizes 4% of the top 200 drugs Highly inducible (some substrates also
autoinduce, and it is also inducible in stressed conditions, e.g. fasting)
High interindividual variation
SubstratesArtemisin Methadone
Bupropion Nicotine
Cyclophosmamide Propofol
Efavirenz Pethidine
Ifosfamide Selegiline
Ketamine Sertraline
Meperidine Tamoxifen
Diazepam Testosterone
Mephenytoin Nevirapine
Aflatoxin b1 MDMA (ecstasy)
Sibutramine
Inhibitors and Inducers of 2B6Inhibitors
Clopidogrel- Potent inhibitor OC/HRT
Efavirenz Paroxetine
Fluoxetine Chlorpyrifos (insecticide)
Fluvoxamine Sertraline
Memantine Thiotepa
Nelfinavir Ticlopidine- Potent inhibitor
Clotrimazole & Itraconazole Raloxifene
Inducers
Lopinavir/Ritonavir Phenytoin
Phenobarbital Rifampin
Dexamethasone Carbamazepine
Metamizole Efavirenz (autoinduces)
Cyclophosphamide (auto) Artemisinin (autoinduces)
Endosulfan
DefinitionsCYPs (or Cytochrome P450 genes) produce enzymes
involved in synthesis and breakdown of molecules and are subdivided into groups and subfamilies (CYP3A4, CYP2C9, etc). Enzymes mostly found in liver, but also found throughout body (brain, intestine, etc). Different combinations of polymorphisms in these genes are haplotypes (CYP2B6*6, CYP2B6*1).
Haplotype= a combination of alleles (DNA sequences) at different places (loci) on the chromosome that are transmitted together
Non-synonymous= a SNP in which both wildtype and mutant forms lead to the same polypeptide sequence is termed synonymous (sometimes called a silent mutation) — if a different polypeptide sequence is produced they are nonsynonymous.
SNP nomenclature:
Haplotypes with decreased activity in vivo
CYP2B6*6, CYP2B6*16, CYP2B6*26
Haplotype with increased activity in vivo
CYP2B6*4
Where haplotypes are important in regard to therapy:Efavirenz for HIV treatmentCyclophosphamide for chemotherapyBupropion for smoking cessationCardiac side effects and death from
methadone
Effect on Efavirenz Therapy CYB2B6*6 haplotype
CYP2B6*6 has two nonsynonymous variants:CYP2B6:516G>T AND CYP2B6:785A>GWith or without additional promoter variants:-1456T>G AND -750T>C or -750T>C
Present in 15-40% Asian, >50% Black population, 26% Caucasian
• Successful Efavirenz dose reduction to 400mg or 200mg was done for CYP2B6*6/*6 and *6/*26 carriers whose EFV concentrations were extremely high (>6000 ng/ml).
Effect on Efavirenz Therapy516G>T
The 516G>T SNP that is present in CYP2B6*6 is also present in *7, *9, and *13
Presence is associated with 3-fold decrease in CYP2B6 activity
The TT genotype is associated with increased efavirenz exposure (resulting in CNS side effects). Also predicts increased risk of developing drug resistance among patients who discontinue efavirenz-containing regimens
983T>CDefining SNP of CYP2B6*18 allele, and found in linkage in
the CYP2B6*16 haplotypeNot observed in Asians, Caucasians. 4-9% Blacks, low
frequency HispanicsAssociated with increased efavirenz and nevirapine
exposure
Effect on Bupropion Therapy CYP2B6*4
Presence of 785A>G SNPHigh frequency in ethnic
groups (15% Asian, 50% Black)Clearance of bupropion increased 1.66-fold
• *1/*4 genotype had AUC of hydroxybupropion (active metabolite formed by 2B6) increased by 25% compared to *1/*1
Effect on Cyclophosphamide Therapy
CYP2B6*6 homozygotes have significantly higher clearance and shorter half-life of cyclophosphamide compared to CYP2B6*1 heterozygotes and homozygotes
Specific SNPs in the promoter region or introns (-2320T>C, -750T>C, 15582C>T of intron 3, or 18492T>C) of CYP2B6 affected cyclophosphamide activation to 4-hydroxycyclophosphamide (AUC of 4-hydroxycyclophosphamide is significantly related to leukocytopenia and neutropenia). This knowledge can help predict adverse effects.
Effect on Doxorubicin and Cyclophosphamide Therapy
Higher dose delay (indicative of higher toxicity) was seen in CYP2B6*2 and CYP2B6*5
CYP2B6*2, CYP2B6*8, CYP2B6*9, CYP2B6*4 were associated with a worse outcome
Bray J, Sludden J, Griffin MJ, Cole M, Verrill M, Jamieson D, Boddy AVInfluence of pharmacogenetics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide. Br J Cancer 2010; 102(6): 1003-1009.
Effect on Methadone TherapyMethadone is a racemic mixture
(R)-methadone: narcotic effect by activating µ-opiod receptor
(S)-methadone: inhibits cardiac potassium channelCYP2B6 is selective for (S)-methadone metabolismHaving decreased CYP2B6 activity increases
plasma concentrations of (S)-methadone (but not (R)-methadone) and increase risk of cardiac side effects and death.*6/*6 genotype had increased risk of prolonged QTc
References Bray J, Sludden J, Griffin MJ, Cole M, Verrill M, Jamieson D, Boddy
AVInfluence of pharmacogenetics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide. Br J Cancer 2010; 102(6): 1003-1009.
Kirchheiner J, Klein C, Meineke I, et al. Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6. Pharmacogenetics. 2003;13:619–26.
T.E. Klein, J.T. Chang, M.K. Cho, K.L. Easton, R. Fergerson, M. Hewett, Z. Lin, Y. Liu, S. Liu, D.E. Oliver, D.L. Rubin, F. Shafa, J.M. Stuart and R.B. Altman, "Integrating Genotype and Phenotype Information: An Overview of the PharmGKB Project" (220k PDF), The Pharmacogenomics Journal 2001; 1:167-170.
Thorn CF, Lamba JK, Lamba V, Klein, Teri E, Altman RB. PharmGKB summary: very important pharmacogene information for CYP2B6. Pharmacogenet Genomics 2010; 20(8):520-523.
Wang H, Tompkins LM. CYP2B6: new insights into a historically overlooked cytochrome P450 isozyme. Curr Drug Metab. 2008;9:598–610.
Wynn, Gary H, Jessica R Oesterheld, Kelly L Cozza, and Scott C Armstrong. Clinical Manual of Drug Interaction Principles for Medical Practice. Washington, DC: American Psychiatric Publishing, 2009.
References Eap CB, Crettol S, Rougier JS, Schlapfer J, Sintra Grilo L, Deglon JJ,
Besson J, Croquette-Krokar M, Carrupt PA, Abriel H. Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers. Clin Pharmacol Ther. 2007;81(5):719–28.
Ribaudo HJ, Haas DW, Tierney C, Kim RB, Wilkinson GR, Gulick RM, Clifford DB, Marzolini C, Fletcher CV, Tashima KT, Kuritzkes DR, Acosta EP. Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group Study. Clin Infect Dis. 2006;42(3):401–7.
Gatanaga H, Hayashida T, Tsuchiya K, Yoshino M, Kuwahara T, Tsukada H, Fujimoto K, Sato I, Ueda M, Horiba M, Hamaguchi M, Yamamoto M, Takata N, Kimura A, Koike T, Gejyo F, Matsushita S, Shirasaka T, Kimura S, Oka S. Clin Infect Dis. 2007;45(9):1230–7.
Nakajima M, Komagata S, Fujiki Y, Kanada Y, Ebi H, Itoh K, Mukai H, Yokoi T, Minami H. Successful efavirenz dose reduction in HIV type 1-infected individuals with cytochrome P450 2B6 *6 and *26. Pharmacogenet Genomics. 2007;17(6):431–45.