title: Carvedilol increases ciclosporin bioavailability by inhibiting P-glycoprotein-mediated transport.
abstract: Carvedilol is often used to treat hypertension and for prophylaxis in vascular sclerosis in renal transplant recipients, who require concomitant treatment with ciclosporin. However, there are few reports regarding the pharmacokinetic interactions between carvedilol and ciclosporin. We have investigated the potential effects of carvedilol on the pharmacokinetics of ciclosporin, and examined the inhibitory effects of carvedilol on P-glycoprotein-mediated transcellular transport using Caco2 cells. Ciclosporin alone or with carvedilol was orally or intravenously administered to rats. The oral administration of carvedilol (10 mg kg(-1)) with ciclosporin (10 mg kg(-1)) increased the whole blood concentration of ciclosporin. When ciclosporin (3 mg kg(-1)) was intravenously administered with carvedilol (3 mg kg(-1)), there was no difference in the whole blood ciclosporin concentration between administration with and without carvedilol. Co-administration with carvedilol increased ciclosporin bioavailability from 33% to 70%. In Caco2 cells, carvedilol caused a concentration-dependent increase in the intracellular accumulation of ciclosporin, and its effect was comparable with that of verapamil. Carvedilol considerably raised the concentration of ciclosporin in the blood and this interaction was associated with the absorption phase of ciclosporin. This interaction was caused by the inhibition of P-glycoprotein-mediated transport by carvedilol in the intestine.
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8560, Japan.
authors.forename: Katsuo
authors.initials: K
authors.lastname: Amioka
authors.forename: Takafumi
authors.initials: T
authors.lastname: Kuzuya
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kushihara
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ejiri
authors.forename: Atsumi
authors.initials: A
authors.lastname: Nitta
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism*; D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D018938:Caco-2 Cells; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002227:Carbazoles / Q000008:administration & dosage / Q000494:pharmacology*; D000077261:Carvedilol; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008297:Male; D011412:Propanolamines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D002227:Carbazoles; D007166:Immunosuppressive Agents; D011412:Propanolamines; D000077261:Carvedilol; D016572:Cyclosporine; D014700:Verapamil