Effects of verapamil on the pharmacokinetics and metabolism of epirubicin.

Experimental data suggest that multidrug resistance in cancer may be overcome by using an increased dose of anticancer agent(s) in combination with a resistance-modifying agent (RMA). We studied the pharmacokinetics and metabolism of both epirubicin (EPI) and verapamil (VPL) to explore the possible pharmacokinetic interactions between these two drugs. Ten patients with advanced breast cancer were given EPI (40 mg/m2 in a daily i.v. bolus for 3 consecutive days), and five of them also received VPL (4 x 120 mg/daily p.o. for 4 consecutive days). The data indicated a significant interaction between these two drugs that affected their metabolism. The areas under the concentration-time curves (AUC) obtained for epirubicin glucuronide, epirubicinol glucuronide, and both of the 7-deoxy-aglycones were higher in the EPI + VPL group as compared with the EPI group. The AUC, terminal half-life, mean residence time, volume of distribution at steady state, and plasma clearance of EPI alone as compared with EPI + VPL did not differ significantly. These results suggest either an induction of enzymes necessary for drug metabolism or an increase in the liver blood flow, resulting in an enhanced generation of metabolites with time or in an inhibition of excretion processes. Comparisons of the AUC values obtained for EPI and its metabolites after the first, second, and third injections of EPI revealed a cumulative effect for the metabolites that was more pronounced in the EPI + VPL group, being significant (P < 0.05) for epirubicin glucuronide in both treatment groups and for epirubicinol glucuronide in the EPI + VPL group. Maximal concentrations of VPL and nor-VPL reached 705 +/- 473 and 308 +/- 122 ng/ml, respectively, with the steady-state concentrations being 265 +/- 42 ng/ml for VPL and 180 +/- 12 ng/ml for nor-VPL.