Effect of P-glycoprotein inhibitor, verapamil, on oral bioavailability and pharmacokinetics of irinotecan in rats

Eur J Pharm Sci. 2009 Mar 2;36(4-5):580-90. doi: 10.1016/j.ejps.2008.12.005. Epub 2008 Dec 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors*
  • Administration, Oral
  • Animals
  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Agents, Phytogenic / pharmacokinetics*
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Area Under Curve
  • Biliary Tract / metabolism
  • Caco-2 Cells
  • Calcium Channel Blockers / administration & dosage
  • Calcium Channel Blockers / pharmacokinetics*
  • Calcium Channel Blockers / pharmacology
  • Camptothecin / administration & dosage
  • Camptothecin / analogs & derivatives*
  • Camptothecin / blood
  • Camptothecin / pharmacokinetics
  • Camptothecin / pharmacology
  • Chromatography, High Pressure Liquid
  • Female
  • Humans
  • Irinotecan
  • Rats
  • Rats, Wistar
  • Spectrophotometry, Ultraviolet
  • Verapamil / pharmacology*


  • ATP Binding Cassette Transporter, Subfamily B
  • Antineoplastic Agents, Phytogenic
  • Calcium Channel Blockers
  • Irinotecan
  • Verapamil
  • Camptothecin