title: Inhibition of transporter-mediated hepatic uptake as a mechanism for drug-drug interaction between cerivastatin and cyclosporin A.
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 [(14)C]CER into human hepatocytes prepared from three different donors was examined. Kinetic analyses revealed K(m) values for the uptake of [(14)C]CER within the range of 3 to 18 microM, 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 K(i) values of 0.3 to 0.7 microM. The uptake of [(14)C]CER was also examined in human organic anion transporting polypeptide-2 (OATP2)-expressing Madin-Darby canine kidney cells (MDCKII). Saturable OATP2-mediated uptake of [(14)C]CER was observed and was also inhibited by CsA, with a K(i) value of 0.2 microM. 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 [(14)C]CER was also examined. The metabolism of [(14)C]CER was inhibited by CsA with an IC(50) value of more than 30 microM. 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.
authors.affiliation: School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Shitara
authors.forename: Tomoo
authors.initials: T
authors.lastname: Itoh
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sato
authors.forename: Albert P
authors.initials: AP
authors.lastname: Li
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D016572:Cyclosporine / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D011725:Pyridines / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D011725:Pyridines; C490280:SLC22A7 protein, human; D016572:Cyclosporine; C086276:cerivastatin