Influence of verapamil on the efflux and metabolism of C-14 moxidectin in cultured rat hepatocytes

Moxidectin (MOX) is an antiparasitic drug widely used in cattle, sheep and companion animals. As a result of the implication of cytochrome P450 3 A in the metabolism of MOX and the role of competitor substrates of P-glycoprot ein (Pgp) in modification of the bioavailability of endectocides, we studie d the influence of verapamil (a multidrug-resistance reversing agent) on th e metabolism of C-14 moxidectin in cultured rat hepatocytes over 72 h. The metabolism of MOX remained low: 10.79 +/- 1.99% of the total C-14 moxidecti n for the main detected metabolite in verapamil-treated cells and 7.17 +/- 0.74% for the control cells after 24 h. The main detected metabolite in rat hepatocytes was the same as that detected in rat hepatic microsomes (the C -29 monohydroxymethyl metabolite). Verapamil increased the quantity of MOX in the cells after 24, 48 and 72 h. Examination of the Area Under the conce ntration time Curve (AUC) of the main detected metabolite revealed a signif icant increase in the exposure of cells to MOX after verapamil treatment th roughout the experiment. It is hypothesized that verapamil interfered with MOX as a substrate for Pgp during the initial incubation period. After this initial interaction, verapamil metabolites were able to interfere with Pgp . This experiment demonstrated the implication of Pgp in the transport of M OX and allowed prediction of the drug-drug interactions which might modify the bioavailability of endectocides.