Drug transporters expressed in the liver play a significant role in the drug disposition of statins, HMG-CoA reductase inhibitors. Rosuvastatin is mainly excreted into bile as parent. It has been shown that rosuvastatin is taken into liver by a carrier-mediated uptake mechanism and has been identified as a substrate for OATP-C/OATP1B1 and other OATPs. However, it is unknown if rosuvastatin is transported by ATP-dependent transporters MDR1/ABCB1, MRP2/ABCC2 and BCRP/ABCG2 expressed at the canalicular membranes. In the present study, we demonstrated that ATP dramatically stimulated rosuvastatin transport in membrane vesicles expressing BCRP. BCRP appears to have two binding or transport sites for rosuvastatin with Km = 14 ÁM for the high affinity site. In contrast, no directional transport of rosuvastatin across MDR1-MDCK cell monolayers and no ATP-dependent transport in the membrane vesicles isolated from the same cells were observed. No MRP2-mediated transport of rosuvastatin in Sf9 membranes was observed. Pharmacokinetic drug-drug interactions between statins and gemfibrozil or cyclosporine have been reported. We further evaluated the effect of selected drugs from clinical drug interaction trials on rosuvastatin uptake in rat hepatocytes and ATP-dependent transport of rosuvastatin in membrane vesicles expressing BCRP. The results suggest that (1) BCRP may contribute to rosuvastatin disposition; and (2) the inhibition of transporters by gemfibrozil and cyclosporine may contribute to the drug-drug interactions observed in the clinic.
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