Transcript PHARMACOGENETICS OF MEMBRANE TRANSPORTERS

PHARMACOGENETICS OF
MEMBRANE TRANSPORTERS
Jeff Idle
Institute of Pharmacology
1st Faculty of Medicine
Charles University, Praha
Proc Natl Acad Sci USA 1915; 1: 235-238
PHARMACOGENETICS
 HUNDREDS OR PROTEINS PARTICIPATE
IN DRUG DISPOSITION
 MOST, IF NOT ALL, DISPLAY GENETIC
POLYMORPHISM
 CRITICAL INTER-PATIENT VARIABILITY
OCCURS WHEN DRUG LEVELS ARE TOO
HIGH/LOW AT SITES OF ACTION
 HISTORICALLY, THIS HAS BEEN
ATTRIBUTED TO A FEW ENZYMES
PHARMACOKINETICS
PROCESS
ENZYMES
TRANSPORTERS
ABSORPTION
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DISTRIBUTION
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METABOLISM
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EXCRETION
ROUTINE PHARMACOGENETICS
 CYP2D6 AND ANTIDEPRESSANTS
 CYP2C9 AND WARFARIN
 TPMT AND AZATHIOPRINE/6-MP
DOSE ADJUSTMENT
EXAMPLES OF DOSE
ADJUSTMENTS
TRANSPORTERS
 30 years ago, drugs seen as subject only to
passive diffusion from one compartment to
another
 pH, pKa (Henderson-Hasselbach equation)
and MW (Fick’s Law of diffusion) were the
guiding principles
 Exceptions were amino acid absorption and
renal excretion of a few drugs
TRANSPORTERS
SLC – SOLUTE TRANSPORTERS
 PASSIVE TRANSPORT, COUPLED TRANSPORT
AND EXCHANGE OF H+, Na+, K+, Ca2+, Zn2+, Cu2+,
Cl-, I-, PO43-, HCO3-, Ach, GABA, choline, Nor, Dop,
5-HT, Gly, Tau, creatine, urea, folate, thiamine,
moncarboxylates, dicarboxylates, citrate, ornithine,
glutamate, aspartate, proline, neutral amino acids,
cationic amino acids, bile acids, fatty acids,
nucleosides, oligopeptides, glucose, organic cations,
acetyl CoA, CMP-sialic acid, UDP-galactose, UDPN-acetylglucosamine, UDP-glucuronic acid, UDP-Nacetylgalactosamine, glycerol-3-phosphate
 AT PLASMA MEMBRANE, MITOCHONDRIAL
MEMBRANE AND VESICULAR MEMBRANES
SLC TRANSPORTERS
 SLC1A1-1A7, SLC2A1-2A14, SLC3A1-2, SLC4A14A11, SLC5A1-5A12, SLC6A1-6A20, SLC7A1-7A14,
SLC8A1-8A3, SLC9A1-9A11, SLC10A1-10A6,
SLC11A1-11A2, SLC12A1-12A9, SLC13A1-13A5,
SLC14A1-14A2, SLC15A1-15A4, SLC16A1-16A14,
SLC17A1-17A8, SLC18A1-18A3, SLC19A1-19A3,
SLC20A1-20A2, SLC22A1-22A18, SLC23A1-23A4,
SLC24A1-24A6, SLC25A1-25A37, SLC26A1-26A11,
SLC27A1-27A6, SLC28A1-28A3, SLC29A1-29A4,
SLC30A1-30A9, SLC31A1-31A2, SLC32A1,
SLC33A1, SLC34A1-34A3, SLC35A1-35A5,
SLC35B1-35B4, SLC35C1-35C2, SLC35D1-35D3,
SLC35E1-35E4, SLC35F1-35F5, SLC36A1-36A4,
SLC37A1-37A4, SLC38A1-38A6, SLC39A1-39A14,
SCL40A1, SCL41A1-41A3, SLC43A1-43A3
SLCO TRANSPORTERS
 PREVIOUSLY GENE FAMILY SLC21
 SOLUTE CARRIER ORGANIC ANION
TRANSPORTER FAMILY
 SLCO1A2, SLCO1B1, SLCO1B3, SLCO1C1,
SLCO2A1, SLCO2B1, SLCO3A1, SLCO4A1,
SLCO4C1, SLCO5A1, SLCO6A1
ABC (ATP-BINDING CASSETTE)
TRANSPORTERS
 ACTIVE EXPORT OF drugs and
foreign chemicals
 AT PLASMA MEMBRANES
ABC TRANSPORTERS
 ABCA1-A13, ABCB1, ABCB4-B11, ABCC1C6, ABCC8-C13, ABCD1-D4, ABCE1,
ABCF1-F3, ABCG1-G5, ABCG8
SLC AND ABC TRANSPORTERS
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SLC transporters
41 families
46 sub-families
316 members
Multiple cellular locations
Import, export, exchange
Wide range of endogenous and
exogenous compounds
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SLCO transporters
6 families
10 sub-families
11 members
Wide range of endogenous and
exogenous anionic compounds
 TOTAL NUMBER OF
TRANSPORTERS
 375 members
ABC transporters
1 family
6 sub-families
48 members
Plasma membrane
Export
Wide range of endogenous
and exogenous compounds
COMMON NAMES AND
ASSOCIATIONS
 ABCB1
 ABCA4
 ABCB1
 ABCC7
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SLC2A1-5
SLC22A1-3
SLC22A6-10
SLC4A1
 SLC6A4
Tangier disease
Stargardt disease (Juvenile
macular degeneration)
Multidrug resistance 1 (MDR1)
Cystic fibrosis transmembrane
conductance regulator (CFTR)
GLUT1-5
OCT1-3
OAT1-5
Erythrocyte membrane protein band 3
(Diego blood group)
Serotonin transporter (SERT)
POLYMORPHISM OF
TRANSPORTER FUNCTION
GENE
TRANSPORTER
DRUGS
EFFECTS OF
SINGLE
NUCLEOTIDE
POLYMORPHISMS
REF.
SLC29A1
ENT1
Nucleoside
analogues
Haplotypes do not
alter uptake of
Ribovirin,
Cytarabine, 5Fluorouridine
Osato et al.
(2003)
SLC6A2
NET1
Noradrenaline
SNP (0.07%)
causes reduced
affinity for Nor
Runkel et al.
(2000)
Paczkowski et
al. (2002)
SLC22A2
OCT2
Procainamide
Cimetidine
Metformin,
Quinidine
Four SNPs reduce
renal elimination
Leabman et al.
(2002)
SLCO1B1
OATP1B1
Pravastatin
17b-estradiol-17bD-glucuronide
SNP markedly
reduces non-renal
clearance
Iwai et al. (2004)
SLC18A2
VMAT2
Reserpine
(inhibitor of
amine uptake)
Two rare SNPs
alter reserpine
inhibition
Burman et al.
(2004)
POLYMORPHISM OF
TRANSPORTER FUNCTION
GENE
TRANSPORTER
DRUGS
EFFECTS OF
SINGLE
NUCLEOTIDE
POLYMORPHISMS
REF.
SLCO1B3
OATP1B3
Digoxin
17b-estradiol-17bD-glucuronide
Taurocholate
Bile acid transport
abolished by 2
SNPs.
Letschert et al.
(2004)
SLC6A4
SERT
5-HT
Haplotype
associated with
Bipolar Affective
Disorder (Taiwan)
Sun et al. (2004)
SLC22A1
OCT1
MPP+
5-HT
SNPs alter
substrate
specificity of OCT1
Kerb et al. (2002)
ABCB1
MDR1
Cyclosporine
Tacrolimus
(calcineurin
inhibitors)
2677TT genotype
associated with
reduced risk of
renal dysfunction
Herbert et al.
(2003)
ABCB1
MDR1
Loperamide
±
Quinidine
2677G/3435T
haplotype
associated with
higher plasma
concentrations
Skarke et al.
(2003)
PERSPECTIVE
 SLC, SLCO, and ABC transporters play a
critical role in drug pharmacokinetics,
affecting absorption, hepatic uptake, hepatic
export, tissue distribution, and renal and
biliary elimination.
 A body of unstructured pharmacogenetic
data is rapidly accumulating that suggests
strongly that membrane transporters are
subject to both genotypic and phenotypic
polymorphism.
PERSPECTIVE
 Genetically-determined variability in drug
and hormone transporter function may
explain major inter-patient variability in drug
pharmacokinetics and susceptibility to drug
resistance and toxicity.
 These differences may be greater than
those due to the known enzyme
polymorphisms.
 There is much to do.