The effect of verapamil on the pharmacokinetics of paclitaxel in rats

The purpose of this study was to investigate the effect of verapamil on the pharmacokinetic parameters of paclitaxel (50 mg/kg) when paclitaxel is co-administered with verapamil (1, 5, and 15 mg/kg) or pretreated with verapamil (5 mg/kg) for 0.5 h, 3 days, and 6 days orally in rats. When paclitaxel was either co-administered or pretreated with verapamil, the peak plasma concentrations (C-max) of paclitaxel with verapamil were significantly higher (p < 0.05 at 5 mg/kg and 0.5 h; p < 0.01 at 15 mg/kg, 3 days and 6 days) than that of the control. The areas under the plasma concentration-time curve (AUC) of paclitaxel with verapamil were significantly (p < 0.05 at 5 mg/kg and 0.5 h; p < 0.01 at 15 mg/kg, 3 days and 6 days) higher than that of the control. The AUCs of paclitaxel were increased with verapamil in the dose dependent manner. The half-life (t(1/2)) of paclitaxel with verapamil was significantly prolonged compared with that of the control, except for 1 mg/kg co-administration. The absolute bioavailability of paclitaxel with verapamil (3.9-5.4%) was significantly (p < 0.05 at 5 mg/kg and 0.5 h; p < 0.01 at 15 mg/kg, 3 days and 6 days) higher than that of the control (2.2%). The relative bioavailability of paclitaxel pretreated with verapamil was higher than that of co-administration in rats. Based on these results, it might be considered that the pharmacokinetic parameters of paclitaxel was significantly affected by verapamil which is an inhibitor of the metabolizing enzyme (CYP3A4) in the intestinal mucosa and liver, and the p-glycoprotein efflux pump in the intestinal mucosa. If these results are confirmed in humans in a clinical setting, the paclitaxel dose should be adjusted when it is given concomitantly with verapamil. (C) 2004 Elsevier B.V All rights reserved.