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Pharmacogenetics of Drug Transporters,Wei Zhang Pharmacogenetics Research Institute Institute of Clinical Pharmacology Central South University,Introduction,Drug transporter,Absorption Distribution Metabolism Excretion,Major drug transporters expressed in the liver,kidney, small intestine and brain,MRP2,Oatp1,2,4/ OATP-C,B,8,OCT1,NTCP,BSEP,MRP2,P-gp/ MDR1,【Small Intestine】,【Blood brain barrier】,【Liver】,【Kidney】,Biliary Excretion,Urinary excretion,OAT2,PEPT1,ASBT,PepT2,OCTN1,2,MRP2,4,OAT1,OCT2,Blood,OAT3,MRP3,BCRP,MRP3,OATPs,OATPs,Absorption,OAT4,BCRP,Mrp1,Bcrp,Oat3,Oatp2/OATP-A,Oatp2/OATP-A,PepT2,Oat3/ OAT3,Oatp3/ OATP-A,Oatp2/ OATP-A,CSF,【Blood-CSF Barrier】,Blood,Mrp1,P-gp/ MDR1,P-gp/ MDR1,P-gp/ MDR1,Organ distribution,Importance of vectorial transport, , ( .,General features,1. Localization in human tissues and basic function,Substrates,Substrates,Substrates,Sites of polymorphisms and allelic frequency in different ethnic populations,Polymorphism of MDR1,Polymorphism of MRP2,Polymorphism of BCRP,Polymorphism of OATP1A2,ND in Asians,Polymorphism of OATP1B1,0.02/0.04,Polymorphism of OATP1B3,Polymorphism of OAT1,Extremely low,Polymorphism of OCT1,Polymorphism of OCT2,Impact of polymorphisms on pharmacotherapy,Pharmacogenetics study of MDR1,Proc Natl Acad Sci. 2000 ;28;97(7):3473-8.,MDR-1 protein expression,AUC,Cmax,The first report on MDR1 C3435T polymorphism,MDR1 3435CT affects mRNA stability,Pharmacogenetics and Genomics 2005, 15:693704,Talinolol Absorption ZWX et al. 2004,ABCB1 C3435T genotype Associated with Aldosterone system in kidney,Pharmacogenetics and Genomics 2007, 17:137144,AIDS therapy With Regards to MDR-1 Polymorphism,Fellay J et al Lancet 2002 Haas et al, 12th CROI, 2005,p = 0.02,CC CT TT,Time to Failure on Efavirenz (n = 340),2. Pharmacogenetics study of OATP1B1,OATP1B1 polymorphism on pravastatin PK & PD,simvastatin acid PK and OATP1B1*17,Pharmacogenetics & Genomics 2006, 16:873879,repaglinide,nateglinide,OATP1B1 polymorphism on oral glucose-lowering drugs,Pharmacogenetics & Genomics 2006,16:683691,Pharmacogenetics of SLCO1B1 haplotypes on irinotecan disposition in Asian cancer patients,Conclusion,The polymorphism of genes encoding drug transporters is a useful marker to interpret large interindividual differences in the pharmacokinetics and response. Except for a few cases (e.g., the SLCO1B1 genotype and statins pharmacokinetics/ pharmacodynamics), there are still discrepancies in the results of functional confirmation of the SNPs. The substrate specificity of most transporters is extremely broad and shows substantial overlap between different members of the superfamily. Multiple gene analysis of the network of genes involved in drug metabolism, transport, and response (e.g., receptors), is preferable.,Thank you !,Difference between BCRP and other ABC transporters:,2 nucleotide-binding domains (NBD) and 12 transmembrane domains (TMD),a single NBD at the amino terminus followed by 6 TMDs,Half-transporter?,Homodimer?,Homotetramer!,J. Biol. Chem. (2004),Int. J. Cancer (2002),C3435T Variation is Associated with Decreased Digoxin Absorption,Sakaeda et al. Pharm. Res. 18:1400-1404, 2001,*Statistically different compared to CC, p 0.05,ABCB1 3435CC Genotype Associated with Epilepsy Drug Resistant,Drug resistant patients more likely to have CC than TT OR 2.66 (1.32-5.38) p = 0.006,Siddiqui et al. NEJM 348:1442-8, 2003,ABCB1 1236/2677/3435 Haplotype Associated with Epilepsy Drug Resistant,Considered 1236-2677-3435 haplotype,Patients with the worst drug resistance more likely to have CGC/CGC haplotype OR 4.67 (1.48 14.75) p = 0.009,Zimprich et al. Neurology 63:1087-1089, 2004,
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