PHARMACOGENETICS OF PHARMACOGENETICS OF MEMBRANE TRANSPORTERSMEMBRANE TRANSPORTERS
Jeff IdleJeff IdleInstitute of PharmacologyInstitute of Pharmacology
11stst Faculty of Medicine Faculty of MedicineCharles University, PrahaCharles University, Praha
PHARMACOGENETICSPHARMACOGENETICS
HUNDREDS OR PROTEINS PARTICIPATE HUNDREDS OR PROTEINS PARTICIPATE IN DRUG DISPOSITIONIN DRUG DISPOSITION
MOST, IF NOT ALL, DISPLAY GENETIC MOST, IF NOT ALL, DISPLAY GENETIC POLYMORPHISMPOLYMORPHISM
CRITICAL INTER-PATIENT VARIABILITY CRITICAL INTER-PATIENT VARIABILITY OCCURS WHEN DRUG LEVELS ARE OCCURS WHEN DRUG LEVELS ARE TOO HIGH/LOW AT SITES OF ACTIONTOO HIGH/LOW AT SITES OF ACTION
HISTORICALLY, THIS HAS BEEN HISTORICALLY, THIS HAS BEEN ATTRIBUTED TO A FEW ENZYMESATTRIBUTED TO A FEW ENZYMES
PHARMACOKINETICSPHARMACOKINETICS
PROCESSPROCESS ENZYMESENZYMES TRANSPORTERSTRANSPORTERS
AABSORPTIONBSORPTION -- ++++
DDISTRIBUTIONISTRIBUTION -- ++++++
MMETABOLISMETABOLISM ++++++ ++
EEXCRETIONXCRETION -- ++++++
ROUTINE PHARMACOGENETICSROUTINE PHARMACOGENETICS
CYP2D6CYP2D6 AND ANTIDEPRESSANTS AND ANTIDEPRESSANTS
CYP2C9CYP2C9 AND WARFARIN AND WARFARIN
TPMTTPMT AND AZATHIOPRINE/6-MP AND AZATHIOPRINE/6-MP
TRANSPORTERSTRANSPORTERS
30 years ago30 years ago, drugs seen as subject only to , drugs seen as subject only to passive diffusion from one compartment to passive diffusion from one compartment to anotheranother
pH, pKa (Henderson-Hasselbach equation) pH, pKa (Henderson-Hasselbach equation) and MW (Fick’s Law of diffusion) were the and MW (Fick’s Law of diffusion) were the guiding principlesguiding principles
Exceptions were amino acid absorption and Exceptions were amino acid absorption and renal excretion of a few drugsrenal excretion of a few drugs
SLC – SOLUTE TRANSPORTERSSLC – SOLUTE TRANSPORTERS
PASSIVE TRANSPORT, COUPLED TRANSPORT PASSIVE TRANSPORT, COUPLED TRANSPORT AND EXCHANGE OFAND EXCHANGE OF H H++, Na, Na++, K, K++, Ca, Ca2+2+, Zn, Zn2+2+, Cu, Cu2+2+, , ClCl--, I, I--, PO, PO44
3-3-, HCO, HCO33--, Ach, GABA, choline, Nor, Dop, , Ach, GABA, choline, Nor, Dop,
5-HT, Gly, Tau, creatine, urea, folate, thiamine, 5-HT, Gly, Tau, creatine, urea, folate, thiamine, moncarboxylates, dicarboxylates, citrate, ornithine, moncarboxylates, dicarboxylates, citrate, ornithine, glutamate, aspartate, proline, neutral amino acids, glutamate, aspartate, proline, neutral amino acids, cationic amino acids, bile acids, fatty acids, cationic amino acids, bile acids, fatty acids, nucleosides, oligopeptides, glucose, organic cations, nucleosides, oligopeptides, glucose, organic cations, acetyl CoA, CMP-sialic acid, UDP-galactose, UDP-acetyl CoA, CMP-sialic acid, UDP-galactose, UDP-NN-acetylglucosamine, UDP-glucuronic acid, UDP--acetylglucosamine, UDP-glucuronic acid, UDP-NN--acetylgalactosamine, glycerol-3-phosphate acetylgalactosamine, glycerol-3-phosphate
AT PLASMA MEMBRANE, MITOCHONDRIAL AT PLASMA MEMBRANE, MITOCHONDRIAL MEMBRANE AND VESICULAR MEMBRANESMEMBRANE AND VESICULAR MEMBRANES
SLC TRANSPORTERSSLC TRANSPORTERS SLC1A1-1A7SLC1A1-1A7, , SLC2A1-2A14SLC2A1-2A14, , SLC3A1-2SLC3A1-2, , SLC4A1-SLC4A1-
4A114A11, , SLC5A1-5A12SLC5A1-5A12, , SLC6A1-6A20SLC6A1-6A20, , SLC7A1-7A14SLC7A1-7A14, , SLC8A1-8A3SLC8A1-8A3, , SLC9A1-9A11SLC9A1-9A11, , SLC10A1-10A6SLC10A1-10A6, , SLC11A1-11A2SLC11A1-11A2, , SLC12A1-12A9SLC12A1-12A9, , SLC13A1-13A5SLC13A1-13A5, , SLC14A1-14A2SLC14A1-14A2, , SLC15A1-15A4SLC15A1-15A4, , SLC16A1-16A14SLC16A1-16A14, , SLC17A1-17A8SLC17A1-17A8, , SLC18A1-18A3SLC18A1-18A3, , SLC19A1-19A3SLC19A1-19A3, , SLC20A1-20A2SLC20A1-20A2, , SLC22A1-22A18SLC22A1-22A18, , SLC23A1-23A4SLC23A1-23A4, , SLC24A1-24A6SLC24A1-24A6, , SLC25A1-25A37SLC25A1-25A37, , SLC26A1-26A11SLC26A1-26A11, , SLC27A1-27A6SLC27A1-27A6, , SLC28A1-28A3SLC28A1-28A3, , SLC29A1-29A4SLC29A1-29A4, , SLC30A1-30A9SLC30A1-30A9, , SLC31A1-31A2SLC31A1-31A2, , SLC32A1SLC32A1, , SLC33A1SLC33A1, , SLC34A1-34A3SLC34A1-34A3, , SLC35A1-35A5SLC35A1-35A5, , SLC35B1-35B4SLC35B1-35B4, , SLC35C1-35C2SLC35C1-35C2, , SLC35D1-35D3SLC35D1-35D3, , SLC35E1-35E4SLC35E1-35E4, , SLC35F1-35F5SLC35F1-35F5, , SLC36A1-36A4SLC36A1-36A4, , SLC37A1-37A4SLC37A1-37A4, , SLC38A1-38A6SLC38A1-38A6, , SLC39A1-39A14SLC39A1-39A14, , SCL40A1SCL40A1, , SCL41A1-41A3SCL41A1-41A3, , SLC43A1-43A3SLC43A1-43A3
SLCO TRANSPORTERSSLCO TRANSPORTERS PREVIOUSLY GENE FAMILY PREVIOUSLY GENE FAMILY SLC21SLC21 SOLUTE CARRIER ORGANIC ANION SOLUTE CARRIER ORGANIC ANION
TRANSPORTER FAMILYTRANSPORTER FAMILY SLCO1A2SLCO1A2, , SLCO1B1SLCO1B1, , SLCO1B3SLCO1B3, , SLCO1C1SLCO1C1, ,
SLCO2A1SLCO2A1, , SLCO2B1SLCO2B1, , SLCO3A1SLCO3A1, , SLCO4A1SLCO4A1, , SLCO4C1SLCO4C1, , SLCO5A1SLCO5A1, , SLCO6A1SLCO6A1
ABC (ATP-BINDING CASSETTE) ABC (ATP-BINDING CASSETTE) TRANSPORTERSTRANSPORTERS
ACTIVE EXPORT OF drugs and ACTIVE EXPORT OF drugs and foreign chemicalsforeign chemicals
AT PLASMA MEMBRANESAT PLASMA MEMBRANES
ABC TRANSPORTERSABC TRANSPORTERS
ABCA1-A13ABCA1-A13, , ABCB1ABCB1, , ABCB4-B11ABCB4-B11, , ABCC1-ABCC1-C6C6, , ABCC8-C13ABCC8-C13, , ABCD1-D4ABCD1-D4, , ABCE1ABCE1, , ABCF1-F3ABCF1-F3, , ABCG1-G5ABCG1-G5, , ABCG8ABCG8
SLC AND ABC TRANSPORTERSSLC AND ABC TRANSPORTERS
SLC transportersSLC transporters 41 families41 families 46 sub-families46 sub-families 316 members316 members Multiple cellular locationsMultiple cellular locations Import, export, exchangeImport, export, exchange
Wide range of endogenous and Wide range of endogenous and exogenous compoundsexogenous compounds
SLCO transportersSLCO transporters 6 families6 families 10 sub-families10 sub-families 11 members11 members Wide range of endogenous and Wide range of endogenous and
exogenous anionic compoundsexogenous anionic compounds
ABC transportersABC transporters 1 family1 family 6 sub-families6 sub-families 48 members48 members Plasma membranePlasma membrane ExportExport
Wide range of endogenous Wide range of endogenous and exogenous compoundsand exogenous compounds
TOTAL NUMBER OF TOTAL NUMBER OF TRANSPORTERSTRANSPORTERS
375 members375 members
COMMON NAMES AND COMMON NAMES AND ASSOCIATIONSASSOCIATIONS
ABCB1ABCB1 Tangier diseaseTangier disease ABCA4ABCA4 Stargardt disease (Juvenile Stargardt disease (Juvenile
macular degeneration)macular degeneration) ABCB1ABCB1 Multidrug resistance 1 (Multidrug resistance 1 (MDR1MDR1)) ABCC7ABCC7 Cystic fibrosis transmembrane Cystic fibrosis transmembrane
conductance regulator (conductance regulator (CFTRCFTR)) SLC2A1-5SLC2A1-5 GLUT1-5GLUT1-5 SLC22A1-3SLC22A1-3 OCT1-3OCT1-3 SLC22A6-10SLC22A6-10 OAT1-5OAT1-5 SLC4A1SLC4A1 Erythrocyte membrane protein band 3 Erythrocyte membrane protein band 3
(Diego blood group)(Diego blood group) SLC6A4SLC6A4 Serotonin transporterSerotonin transporter ((SERTSERT))
POLYMORPHISM OF POLYMORPHISM OF TRANSPORTER FUNCTIONTRANSPORTER FUNCTION
GENEGENE TRANSPORTERTRANSPORTER DRUGSDRUGS EFFECTS OF EFFECTS OF SINGLE SINGLE
NUCLEOTIDE NUCLEOTIDE POLYMORPHISMSPOLYMORPHISMS
REF.REF.
SLC29A1SLC29A1 ENT1ENT1 Nucleoside Nucleoside analoguesanalogues
Haplotypes do not Haplotypes do not alter uptake of alter uptake of
Ribovirin, Ribovirin, Cytarabine, 5-Cytarabine, 5-FluorouridineFluorouridine
Osato Osato et alet al. . (2003)(2003)
SLC6A2SLC6A2 NET1NET1 NoradrenalineNoradrenaline SNP (0.07%) SNP (0.07%) causes reduced causes reduced affinity for Noraffinity for Nor
Runkel Runkel et al.et al. (2000)(2000)
Paczkowski Paczkowski et et al.al. (2002) (2002)
SLC22A2SLC22A2 OCT2OCT2 ProcainamideProcainamideCimetidineCimetidineMetformin,Metformin, QuinidineQuinidine
Four SNPs reduce Four SNPs reduce renal eliminationrenal elimination
Leabman Leabman et alet al. . (2002)(2002)
SLCO1B1SLCO1B1 OATP1B1OATP1B1 PravastatinPravastatin1717-estradiol-17-estradiol-17--
D-glucuronideD-glucuronide
SNP markedly SNP markedly reduces non-renal reduces non-renal
clearanceclearance
Iwai Iwai et alet al. (2004). (2004)
SLC18A2SLC18A2 VMAT2VMAT2 Reserpine Reserpine (inhibitor of (inhibitor of
amine uptake)amine uptake)
Two rare SNPs Two rare SNPs alter reserpine alter reserpine
inhibitioninhibition
Burman Burman et alet al. . (2004)(2004)
POLYMORPHISM OF POLYMORPHISM OF TRANSPORTER FUNCTIONTRANSPORTER FUNCTION
GENEGENE TRANSPORTERTRANSPORTER DRUGSDRUGS EFFECTS OF EFFECTS OF SINGLE SINGLE
NUCLEOTIDE NUCLEOTIDE POLYMORPHISMSPOLYMORPHISMS
REF.REF.
SLCO1B3SLCO1B3 OATP1B3OATP1B3 DigoxinDigoxin1717-estradiol-17-estradiol-17--
D-glucuronideD-glucuronideTaurocholateTaurocholate
Bile acid transport Bile acid transport abolished by 2 abolished by 2
SNPs. SNPs.
Letschert Letschert et alet al. . (2004)(2004)
SLC6A4SLC6A4 SERTSERT 5-HT5-HT Haplotype Haplotype associated with associated with Bipolar Affective Bipolar Affective Disorder (Taiwan)Disorder (Taiwan)
Sun Sun et alet al. (2004). (2004)
SLC22A1SLC22A1 OCT1OCT1 MPPMPP++
5-HT5-HT
SNPs alter SNPs alter substrate substrate
specificity of OCT1specificity of OCT1
Kerb Kerb et alet al. . (2002)(2002)
ABCB1ABCB1 MDR1MDR1 CyclosporineCyclosporineTacrolimusTacrolimus(calcineurin (calcineurin inhibitors)inhibitors)
2677TT genotype 2677TT genotype associated with associated with reduced risk of reduced risk of
renal dysfunctionrenal dysfunction
Herbert Herbert et alet al. . (2003)(2003)
ABCB1ABCB1 MDR1MDR1 LoperamideLoperamide±±
QuinidineQuinidine
2677G/3435T 2677G/3435T haplotype haplotype
associated with associated with higher plasma higher plasma concentrationsconcentrations
Skarke Skarke et alet al. . (2003)(2003)
PERSPECTIVEPERSPECTIVE
SLC, SLCO, and ABC transporters play a SLC, SLCO, and ABC transporters play a critical role in drug pharmacokinetics, critical role in drug pharmacokinetics, affecting absorption, hepatic uptake, hepatic affecting absorption, hepatic uptake, hepatic export, tissue distribution, and renal and export, tissue distribution, and renal and biliary elimination.biliary elimination.
A body of unstructured pharmacogenetic A body of unstructured pharmacogenetic data is rapidly accumulating that suggests data is rapidly accumulating that suggests strongly that membrane transporters are strongly that membrane transporters are subject to both genotypic and phenotypic subject to both genotypic and phenotypic polymorphism.polymorphism.
PERSPECTIVEPERSPECTIVE
Genetically-determined variability in drug Genetically-determined variability in drug and hormone transporter function may and hormone transporter function may explain major inter-patient variability in drug explain major inter-patient variability in drug pharmacokinetics and susceptibility to drug pharmacokinetics and susceptibility to drug resistance and toxicity.resistance and toxicity.
These differences may be greater than These differences may be greater than those due to the known enzyme those due to the known enzyme polymorphisms.polymorphisms.
There is much to do.There is much to do.