title: Long-lasting inhibitory effects of cyclosporin A, but not tacrolimus, on OATP1B1- and OATP1B3-mediated uptake.
abstract: Cyclosporin A (CsA) causes a number of clinically relevant drug-drug interactions (DDIs) by inhibiting OATP1B1 and OATP1B3. In the present study, long-lasting inhibitory effects of CsA on these transporters were examined in comparison to tacrolimus (TCR). OATP1B1- and OATP1B3-expressing HEK293T cells, OATP1B1-expressing MDCK II cells, and human hepatocytes were preincubated with CsA or TCR, and uptake studies were carried out in their presence or absence. Western blot or immunohistochemical studies were done in OATP1B1-expressing HEK293T cells. The pretreatment of OATP1B1- and OATP1B3-expressing cells with 0.5-10 µM CsA, but not TCR, resulted in a reduction in their activity, even after washing out CsA from the incubation media. Preincubating the cells with CsA significantly enhanced its inhibitory effects on OATP1B1 and OATP1B3 by coincubation at 0.1-1 µM. Preincubation with 1 µM CsA caused a reduction in OATP1B1 activity for at least 18 h after its removal. The expression of OATP1B1 was not affected by incubation with CsA and no obvious change in its intracellular localization was observed. The long-lasting inhibition by CsA was also observed in human hepatocytes. Thus, CsA has a long-lasting inhibitory effect on OATP1B1 and OATP1B3. It may attribute to the clinically relevant DDIs between OATP substrates and CsA.
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Shitara
authors.forename: Kumiko
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Nagamatsu
authors.forename: Satomi
authors.initials: S
authors.lastname: Wada
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Horie
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016572:Cyclosporine / Q000494:pharmacology*; D004285:Dogs; D004347:Drug Interactions; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007700:Kinetics; D027381:Liver-Specific Organic Anion Transporter 1; D061985:Madin Darby Canine Kidney Cells; D008954:Models, Biological; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012844:Sincalide / Q000378:metabolism; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D016559:Tacrolimus / Q000494:pharmacology*; D014162:Transfection
chemical_list: D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D004970:Estrone; D016572:Cyclosporine; D012844:Sincalide; C017296:estrone sulfate; D016559:Tacrolimus