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

Proc Natl Acad Sci USA 1915; 1: 235-238

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

DOSE ADJUSTMENTDOSE ADJUSTMENT

EXAMPLES OF DOSE EXAMPLES OF DOSE ADJUSTMENTSADJUSTMENTS

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

TRANSPORTERSTRANSPORTERS

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.