Multiple OATP transporters mediate the cellular uptake of rosuvastatin

Abstract

Rosuvastatin is an HMG-CoA reductase inhibitor (statin) used in the treatment of hypercholesterolemia. Rosuvastatin is not subject to significant metabolism; therefore its disposition is thought to be highly dependent on drug transporters expressed in organs such as the intestine, liver, and kidney. Recent studies have shown that OATP1B1 (OATP-C) can mediate the hepatic uptake of this drug. However, the extent and relevance of other OATP transporters to the disposition of this drug has not been clarified. In this study, we expressed an array of human and rat Organic Anion Transporting Polypeptide (OATP) transporters using a recombinant vaccinia system. As expected, we are able to confirm that human OATP1B1 is able to mediate the cellular uptake of rosuvastatin. In addition, human OATP1A2 (OATP-A), OATP2B1 (OATP-B), OATP1B3 (OATP-8), as well as rat Oatp1a1 (Oatp1), Oatp1a4 (Oatp2), Oatp1a5 (Oatp3), and Oatp1b2 (Oatp4) were also capable of rosuvastatin uptake. When we expressed allelic variants of human OATP1B1, profound loss of rosuvastatin uptake was noted in cells expressing *5, *9, *15, and *16 (*1b+*9) variants. Accordingly, our findings would suggest multiple OATP transporters mediate the uptake of rosuvastatin from the GI tract and liver. Moreover, involvement of other hepatic OATP transporters is likely to attenuate the impact of SLCO1B1 (OATP-C) SNPs to the overall disposition of rosuvastatin in vivo. Clinical Pharmacology & Therapeutics (2005) 77, P64–P64; doi: 10.1016/j.clpt.2004.12.136