title: In vitro and in vivo correlation of the inhibitory effect of cyclosporin A on the transporter-mediated hepatic uptake of cerivastatin in rats.
abstract: Previously, we have shown that the inhibition of the transporter-mediated hepatic uptake of cerivastatin (CER) by cyclosporin A (CsA) could, at least partly, explain a pharmacokinetic interaction between these drugs in humans. In the present study, we have examined the effect of CsA on the in vivo disposition of CER in rats and the in vitro uptake of [14C]CER in isolated rat hepatocytes in an attempt to evaluate the effect of inhibition of transporter-mediated hepatic uptake on the in vivo CER disposition. The steady-state plasma concentration of CER increased 1.4-fold when coadministered with CsA up to a steady-state blood concentration of 4 microM. Studies of [14C]CER uptake into isolated rat hepatocytes showed saturable transport, with the saturable portion accounting for more than 80% of the total uptake. CsA competitively inhibited the uptake of [14C]CER with a Ki of 0.3 microM. The IC50 for the uptake of [14C]CER in the absence and presence of rat plasma was 0.2 and 2.3 microM, respectively. The in vivo hepatic uptake of [14C]CER evaluated by the liver uptake index method was also inhibited by CsA in a dose-dependent manner. On the other hand, CsA did not inhibit the metabolism of [14C]CER in rat microsomes. The in vitro and in vivo correlation analysis revealed that this pharmacokinetic interaction between these drugs in rats could be quantitatively explained by the inhibition of transporter-mediated hepatic uptake. Thus, this drug-drug interaction in rats is predominantly caused by the transporter-mediated uptake process.
authors.affiliation: School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Shitara
authors.forename: Masaru
authors.initials: M
authors.lastname: Hirano
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Adachi
authors.forename: Tomoo
authors.initials: T
authors.lastname: Itoh
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sato
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000465:Algorithms; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D011485:Protein Binding; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D029362:Organic Anion Transporters, Sodium-Independent; D011725:Pyridines; C421102:Slco1a1 protein, rat; D013739:Testosterone; D016572:Cyclosporine; C086276:cerivastatin