Inhibition of Transporter-Mediated Hepatic Uptake as a Mechanism for Drug-Drug Interaction between Cerivastatin and Cyclosporin A
- 1Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (Y.Sh., Y.Su.); 2Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Saitama, Japan (Y.Sh., Y.Su.); 3School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan (T.I.); 4Faculty of Pharmaceutical Sciences, Showa University, Tokyo, Japan (H.S.); and 5In Vitro Technologies, Inc., Baltimore, Maryland (A.P.L.)
- 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
Abstract
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 revealedKm 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 withKi 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 IC50value 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.
Footnotes
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↵1 Present address: Faculty of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
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↵2 Present address: Phase 1 Molecular Toxicology, Inc., Santa Fe, NM.
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DOI: 10.1124/jpet.102.041921
- Abbreviations:
- HMG-CoA
- 3-hydroxy-3-methylglutaryl-coenzyme A
- DDI
- drug-drug interaction
- CER
- cerivastatin
- CsA
- cyclosporin A
- OATP
- organic anion transporting polypeptide
- MDCK
- Madin-Darby canine kidney
- OAT
- organic anion transporter
- AUC
- area under plasma concentration-time curve
- CL
- clearance
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- Received July 23, 2002.
- Accepted October 28, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
