药物转运体的遗传药理学-transporter.ppt

Drug transporter AIDS therapy With Regards to MDR-1 Polymorphism ABCB1 3435CC Genotype Associated with Epilepsy Drug Resistant ABCB1 1236/2677/3435 Haplotype Associated with Epilepsy Drug Resistant ABCB1 C3435T genotype Associated with Aldosterone system in kidney Pharmacogenetics and Genomics 2007, 17:137–144 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, 16:873–879 repaglinide nateglinide OATP1B1 polymorphism on oral glucose-lowering drugs Pharmacogenetics Genomics 2006,16:683–691 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 ! Exon 26 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 5.74 ± 3.04 5.8 ± 1.94 8.84 ± 3.28 AUC0-24h (ng h/ml) 3.27 ± 0.58* 3.20 ± 0.49* 4.11 ± 0.57 AUC0-4h (ng h/ml) TT (n=6) CT (n=4) CC (n=5) Sakaeda et al. Pharm. Res. 18:1400-1404, 2001 *Statistically different compared to CC, p