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 14 C-pravastatin by human hepatocytes with K-i values of 31.7 mu M and 15.7 mu M, respectively and also inhibited pravastatin uptake by OATP1B1-expressing Xenopus laevis oocytes with K-i values of 15.1 mu M and 7.6 mu M. 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-M3 did not affect the biliary transport of pravastatin by MRP2. Considering the plasma concentrations of gemfibrozil and gem-glu in humans, the inhibition of OATP1B1- mediated hepatic uptake of pravastatin by gem-glu would contribute, at least in part, to the elevation of plasma concentration of pravastatin by the concomitant use of gemfibrozil.