Gemfibrozil and its glucuronide inhibit the hepatic uptake of pravastatin mediated by OATP1B1

When pravastatin (40 mg/day) was co-administered with gemfibrozil (600 mg, b.i.d., 3 days) to man, the AUC of pravastatin increased approximately 2-fold. We have clarified that OATP1B1 is a key determinant of the hepatic uptake of pravastatin in humans. Thus, we hypothesized that gemfibrozil and the main plasma metabolites, a glucuronide (gem-glu) and a carboxylic acid metabolite (gem-M3), might inhibit the hepatic uptake of pravastatin and lead to the elevation of the plasma concentration of pravastatin. Gemfibrozil and gem-glu inhibited the uptake of 14C-pravastatin by human hepatocytes with Ki values of 31.7 µM and 15.7 µM, respectively and also inhibited pravastatin uptake by OATP1B1-expressing Xenopus laevis oocytes with Ki values of 15.1 µM and 7.6 µM. Additionally, we examined the biliary transport of pravastatin and demonstrated that pravastatin was transported by MRP2 using both human canalicular membrane vesicles (hCMVs) and human MRP2-expressing vesicles. However, gemfibrozil, gem-glu and gem-M...