title: Influence of verapamil on the efflux and metabolism of 14C moxidectin in cultured rat hepatocytes.
abstract: 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-glycoprotein (Pgp) in modification of the bioavailability of endectocides, we studied the influence of verapamil (a multidrug-resistance reversing agent) on the metabolism of 14C moxidectin in cultured rat hepatocytes over 72 h. The metabolism of MOX remained low: 10.79 +/- 1.99% of the total 14C moxidectin 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 C29 monohydroxymethyl metabolite). Verapamil increased the quantity of MOX in the cells after 24, 48 and 72 h. Examination of the Area Under the concentration time Curve (AUC) of the main detected metabolite revealed a significant increase in the exposure of cells to MOX after verapamil treatment throughout 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 MOX and allowed prediction of the drug-drug interactions which might modify the bioavailability of endectocides.
authors.affiliation: INRA-Toulouse, Laboratoire de Pharmacologie-Toxicologie, 180 Chemin de Tournefeuille, B.P. 3, Toulouse Cedex 9, France.
authors.forename: J
authors.initials: J
authors.lastname: Dupuy
authors.forename: G
authors.initials: G
authors.lastname: Larrieu
authors.forename: J F
authors.initials: JF
authors.lastname: Sutra
authors.forename: C
authors.initials: C
authors.lastname: Eeckhoutte
authors.forename: M
authors.initials: M
authors.lastname: Alvinerie
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000871:Anthelmintics / Q000493:pharmacokinetics*; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D004347:Drug Interactions; D022781:Hepatocytes / Q000378:metabolism*; D018942:Macrolides; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014700:Verapamil / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000871:Anthelmintics; D000900:Anti-Bacterial Agents; D002250:Carbon Radioisotopes; D018942:Macrolides; D014700:Verapamil; C027837:moxidectin