title: Effect of P-glycoprotein inhibitor, verapamil, on oral bioavailability and pharmacokinetics of irinotecan in rats.
abstract: The objective of present investigation was to study the effect of verapamil on the pharmacokinetics of irinotecan in order to evaluate the role of P-glycoprotein (P-gp) in irinotecan disposition. An in vitro study using Caco-2 intestinal cell monolayer was first carried out to determine the effect of verapamil on the function of intestinal P-gp. Verapamil (25mg/kg) was administered orally 2h before irinotecan oral (80 mg/kg) or intravenous (20mg/kg) dosing in female Wistar rats. Plasma and biliary samples were collected at specified time points from control and treated animals to determine irinotecan and its metabolite, SN-38 concentrations. Bi-directional transport and inhibition studies in Caco-2 cells indicated irinotecan to be a P-gp substrate and the function of intestinal P-gp was significantly inhibited in presence of verapamil. After oral irinotecan dosing, the mean area under the plasma concentration-time curve (AUC) was found to be 14.03+/-2.18 microgh/ml which was increased significantly, i.e. 61.71+/-15.0 microgh/ml when verapamil was co-administered (P<0.05). Similarly, the mean maximum plasma concentration of irinotecan increased from 2.93+/-0.37 microg/ml (without verapamil) to 10.75+/-1.0 microg/ml (with verapamil) (P<0.05). There was approximately 4-5-folds increase in apparent bioavailability. On the other hand, the intravenous irinotecan administration with verapamil resulted in small but statistically significant effect on AUC (10.76+/-2.0 to 23.3+/-3.8 microgh/ml; P<0.05) and systemic clearance (1206.4+/-159.7 to 713.5+/-78.2 ml/(hkg)). In addition, SN-38 showed significant change in oral pharmacokinetic parameters and minor changes in intravenous pharmacokinetic profile. Biliary excretion curves of both irinotecan and SN-38 were lowered by verapamil. The mean percent of irinotecan excreted into bile over 5h following intravenous and oral administration was found to be 8% and 1%, respectively, which was further reduced to half when treated with verapamil. These results are quite stimulating for further development of a clinically useful oral formulation of irinotecan based on P-gp inhibition.
authors.affiliation: Dept. of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi 110062, India.
authors.forename: Tripta
authors.initials: T
authors.lastname: Bansal
authors.forename: Gautam
authors.initials: G
authors.lastname: Mishra
authors.forename: Manu
authors.initials: M
authors.lastname: Jaggi
authors.forename: Roop K
authors.initials: RK
authors.lastname: Khar
authors.forename: Sushama
authors.initials: S
authors.lastname: Talegaonkar
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001659:Biliary Tract / Q000378:metabolism; D018938:Caco-2 Cells; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D000077146:Irinotecan; D051381:Rats; D017208:Rats, Wistar; D013056:Spectrophotometry, Ultraviolet; D014700:Verapamil / Q000494:pharmacology*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000972:Antineoplastic Agents, Phytogenic; D002121:Calcium Channel Blockers; D000077146:Irinotecan; D014700:Verapamil; D002166:Camptothecin