Examining the regulation of hepatic drug disposition and metabolism by organic anion transporting polypeptide, P-glycoprotein and multidrug resistance-associated protein 2.

摘要

There are many examples of clinical drug interactions at the level of metabolizing enzymes such as cytochrome P450 and much effort during drug development has been focused on determining the potential interactions between new drug molecules with enzymes. However, it now appears that members of the OATP uptake transporter family, as well as certain efflux pumps including P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) are also key players in affecting drug disposition in the liver besides enzymes. We hypothesized that inhibition of hepatic uptake or efflux transporters would modify the disposition and metabolism of drugs.; My dissertation research primarily used the isolated perfused rat liver (IPRL) system, which retains all the relevant transporters and enzymes, to examine the pharmacokinetic changes at the organ level. The results from IPRL studies with digoxin with and without transporter inhibitors showed that inhibition of Oatp1a4 by rifampicin and P-gp by quinidine affects CYP3A metabolism significantly by decreasing and increasing clearance, respectively. The same perfused liver system was also applied to atorvastatin, a compound that acts as a substrate of multiple transporters including Oatp, P-gp and Mrp2, as validated by cellular assays. Our data suggested that the Oatp-mediated uptake of both atorvastatin and its metabolites was inhibited by rifampicin. However, the extent of metabolism was significantly reduced as reflected by the reduced amounts of metabolites detected in rifampicin-treated livers.; Following an in vivo study examining the influence of rifampicin in reducing the clearance and metabolism of atorvastatin in rats, a clinical study was conducted to determine if the liver-specific transporter, OATP1B1, represents the major hepatic uptake system for atorvastatin and its active metabolites in humans. Our results demonstrated that acute inhibition of OATP1B1 caused a 6-fold increase in the exposure of atorvastatin and its metabolites. These data emphasize the relevance of OATP in affecting the hepatic elimination of atorvastatin. Metabolites of atorvastatin undergo similar disposition pathways as the parent drug.; Overall, the results from the IPRL study correlates well with in vivo studies and support our hypothesis that transporters are the major players in hepatic drug elimination, even for substrates that undergo extensive metabolism.