title: Preincubation-dependent and long-lasting inhibition of organic anion transporting polypeptide (OATP) and its impact on drug-drug interactions.
abstract: Preincubation with cyclosporin A (CsA), a potent inhibitor of organic anion transporting polypeptide 1B1 (OATP1B1) and OATP1B3, enhanced its inhibitory effects on these transporters in vitro. A similar effect was observed upon preincubation with some other inhibitors. Removing these from the incubation media did not readily reverse the inhibition on OATP1B1 and OATP1B3. This preincubation-dependent long-lasting inhibition appeared to be related to CsA concentration in the cells in addition to that in the incubation media. Thus, we hypothesized that CsA inhibits OATP1B1 and OATP1B3 from inside (trans-inhibition) as well as outside (cis-inhibition) the cells and constructed the cis- and trans-inhibition model. The enhanced inhibitory effect of CsA on OATP1B1 observed after preincubation was quantitatively described using Ki,outand Ki,inas inhibition constants for cis- and trans-inhibitions, respectively. In addition, a long-lasting inhibition was also described by this model. Additional factors taken into consideration when simulating in vivo pharmacokinetic alterations by CsA are potential inhibition by AM1, a major metabolite of CsA, which has been reported to inhibit OATP1B1 and OATP1B3. Based on the physiologically based pharmacokinetic model incorporating trans- and cis-inhibition of OATP1B1 by CsA, the simulation showed that OATP1B1-mediated drug-drug interaction with CsA was suggested to be time-dependent also in vivo although further clinical studies are required for confirmation.
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Translational Medicine and Early Development, R&D Operations, Sanofi, Tokyo, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Shitara
authors.affiliation: Sugiyama Laboratory, RIKEN Innovation Center, RIKEN, Yokohama, Japan. Electronic address: ychi.sugiyama@riken.jp.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D027361:Organic Anion Transporters; D016572:Cyclosporine
keywords: Drug–drug interactions; Hepatic uptake; Long-lasting inhibition; Modeling & simulation; OATP1B1; Physiologically based pharmacokinetic model; Time-dependent inhibition