title: Long-lasting inhibition of the intestinal absorption of fexofenadine by cyclosporin A in rats.
abstract: The purpose of the present study is to examine the long-lasting inhibition of intestinal organic anion transporting polypeptides (Oatps) by cyclosporin A (CsA) in rats using fexofenadine (FEX) as a probe drug. We examined the pharmacokinetics of FEX after its intravenous or oral administration to rats at 3 or 24 h after the oral administration of CsA. When FEX was administered at 3 h after the administration of CsA, its plasma concentration increased regardless of whether it was administered intravenously or orally. When FEX was intravenously administered at 24 h after the oral administration of CsA, its plasma concentration was increased; however, that observed after its oral administration was not significantly different from the vehicle-treated control. When FEX was administered at 3 h after the administration of CsA, the hepatic availability (F(h)) and the fraction absorbed in the intestine as an unchanged form (F(a)·F(g)) of FEX were increased, resulting in increased bioavailability (=F(a)·F(g)·F(h)). At 24 h after the administration of CsA, the F(h) of FEX was increased, whereas its bioavailability was decreased, suggesting that its F(a)·F(g) was decreased because of the long-lasting inhibition. In conclusion, CsA has long-lasting inhibitory effects on Oatps in the rat intestine as well as in the liver.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Suzuki
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Shitara
authors.forename: Kousuke
authors.initials: K
authors.lastname: Fukuda
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Horie
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018926:Anti-Allergic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016593:Terfenadine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D018926:Anti-Allergic Agents; D000935:Antifungal Agents; D027361:Organic Anion Transporters; D012333:RNA, Messenger; D016593:Terfenadine; D016572:Cyclosporine; C093230:fexofenadine