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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (Y.Sh., Y.Su.); Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Saitama, Japan (Y.Sh., Y.Su.); School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan (T.I.); Faculty of Pharmaceutical Sciences, Showa University, Tokyo, Japan (H.S.); and In Vitro Technologies, Inc., Baltimore, Maryland (A.P.L.)
The mechanism involved in the clinically relevant drug-drug interaction (DDI) between cerivastatin (CER) and cyclosporin A (CsA) has not yet been clarified. In the present study, we examined the possible roles of transporter-mediated hepatic uptake in this DDI. The uptake of [14C]CER into human hepatocytes prepared from three different donors was examined. Kinetic analyses revealed Km values for the uptake of [14C]CER within the range of 3 to 18 µM, suggesting that more than 70% of the total uptake at therapeutic CER concentrations was accounted for by a saturable process, i.e., transporter-mediated uptake. This uptake was inhibited by CsA with Ki values of 0.3 to 0.7 µM. The uptake of [14C]CER was also examined in human organic anion transporting polypeptide-2 (OATP2)-expressing Madin-Darby canine kidney cells (MDCKII). Saturable OATP2-mediated uptake of [14C]CER was observed and was also inhibited by CsA, with a Ki value of 0.2 µM. These results suggest that the DDI between CER and CsA involves the inhibition of transporter-mediated uptake of CER and, at least in part, its OATP2-mediated uptake. The effect of CsA on the in vitro metabolism of [14C]CER was also examined. The metabolism of [14C]CER was inhibited by CsA with an IC50 value of more than 30 µM. From these results, we conclude that the DDI between CER and CsA is mainly due to the inhibition of transporter (at least partly OATP2)-mediated uptake in the liver.
Address correspondence to: Dr. Yuichi Sugiyama, Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: sugiyama{at}mol.f.u-tokyo.ac.jp
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