Received for publication March 11, 2008.
Revised June 13, 2008.
Accepted for publication July 7, 2008.

Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin

Abstract

Rosuvastatin is an HMG-CoA reductase inhibitor and one of the most hydrophilic of the commercially available statins. It is efficiently accumulated in the liver and excreted into the bile in an unchanged form in rats, suggesting that hepatic transporters play a major role in the clearance of rosuvastatin. Therefore, we investigated the transporters responsible for the hepatic uptake and biliary excretion of rosuvastatin. Uptake studies revealed that human organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and OATP2B1 accept rosuvastatin as a substrate. Among the OATP family transporters, OATP1B1 contributes predominantly to the hepatic uptake of rosuvastatin, as estimated with the previously published relative activity factor method (Hirano et al., 2004), and OATP1B3 is also partly involved. Significant vectorial basal-to-apical transport was observed in OATP1B1/MRP2, OATP1B1/MDR1, and OATP1B1/BCRP double transfectants compared with that in an OATP1B1 single transfectant or in vector-transfected control cells. The ATP-dependent uptake of rosuvastatin by human breast cancer resistance protein (BCRP)-expressing membrane vesicles was significantly higher than the uptake by GFP-expressing control vesicles, suggesting that MRP2, MDR1, and BCRP can transport rosuvastatin. Under in vivo conditions, the biliary excretion clearance based on the intrahepatic concentration of parent rosuvastatin in Eisai hyperbilirubinemic rats and Bcrp1-knockout mice was reduced to 53% and 12% of that in the control SD rats and FVB mice, respectively, indicating that rat Mrp2 and mouse Bcrp1 are both partly involved in the biliary excretion of rosuvastatin. These results suggest that multiple transporters are involved in the hepatic uptake and efflux of rosuvastatin.

Key words: ABC transporters, biliary excretion, hepatic uptake, hepatobiliary transport, organic anion transport, transporters

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