title: Contributions of intestinal P-glycoprotein and CYP3A to oral bioavailability of cyclosporin A in mice treated with or without dexamethasone.
abstract: The contributions of P-glycoprotein (P-gp) and CYP3A to the oral bioavailability (BA) of cyclosporin A (CyA) were separately evaluated by using wild-type and mdr1a/1b knockout mice treated with dexamethasone (DEX). Mice were treated with DEX (1 or 75 mg/kg/day, i.p.) daily for 7 days, and the blood concentrations of CyA were measured after an i.v. or p.o. dose of CyA (10mg/kg) at 1.5h after the last DEX treatment. The BA values of CyA in wild-type and mdr1a/1b knockout mice were similar, 0.25 and 0.287, respectively. As regards expression of mdr1a and CYP3A mRNAs, expression of mdr1a mRNA was weakest in the duodenum, the main absorption site of CyA, along the whole intestine of wild-type mice, while expression of CYP3A was strongest in the duodenum of both types of mice. After treatment with 1 and 75 mg/kg DEX, the BA values decreased to 43 and 25% of the control in wild-type mice, respectively, and to 89 and 73% of the control in mdr1a/1b knockout mice, respectively. Expression of mdr1a mRNA in duodenum of wild-type mice was potently induced by DEX treatment. The expression of CYP3A mRNA in liver and duodenum of both strains was enhanced only by high-DEX treatment. These results suggest that P-glycoprotein plays only a small role in the absorption of CyA under physiological conditions, but the protein is readily induced by DEX and then functions as a more substantial absorption barrier to CyA than does CYP3A in the intestine.
authors.affiliation: Department of Clinical Pharmacy, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan.
authors.forename: Mingji
authors.initials: M
authors.lastname: Jin
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Shimada
authors.forename: Koichi
authors.initials: K
authors.lastname: Yokogawa
authors.forename: Masaaki
authors.initials: M
authors.lastname: Nomura
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kato
authors.forename: Akira
authors.initials: A
authors.lastname: Tsuji
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Miyamoto
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D000097202:ATP-Binding Cassette Sub-Family B Member 4; D008565:Membrane Proteins
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D003907:Dexamethasone; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins