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

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 (25 mg/kg) was administered orally 2 h before irinotecan oral (80 mg/kg) or intravenous (20 mg/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 μg h/ml which was increased significantly, i.e. 61.71 ± 15.0 μg h/ml when verapamil was co-administered (P < 0.05). Similarly, the mean maximum plasma concentration of irinotecan increased from 2.93 ± 0.37 μg/ml (without verapamil) to 10.75 ± 1.0 μg/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 μg h/ml; P < 0.05) and systemic clearance (1206.4 ± 159.7 to 713.5 ± 78.2 ml/(h kg)). 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 5 h 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.