Comparative assesment of hepatic and ruminal metabolism of the novel anthelmintic monepantel in sheep and cattle

VIRKEL G.; BALLENT M.; MATÉ L.; VIVIANI P.; LANUSSE C.; LIFSCHITZ A.

Nantes

Congreso; 13th International Congress of the European Association for Veterinary Pharmacology and Toxicology; 2014

13th International Congress of the European Association for Veterinary Pharmacology and Toxicology

Introduction: Monepantel (MNP) is a novel anthelmintic compound with activity against a wide range of gastro-intestinal nematodes including those are resistant to the macrocyclic lactones, benzimidazoles and levamisole. The plasma disposition kinetics, distribution to target tissues and metabolism of MNP were recently characterized in sheep. The current work assessed the comparative hepatic sulphonation of MNP in sheep and cattle. The chemical stability of both MNP and its main metabolite monepantel sulphone (MNPSO2) in ruminal fluid from both ruminant species was also investigated. Material and methods: Microsomal fractions from sheep (n=5) and cattle (n=5) liver were performed by differential ultracentrifugation. The microsomal biotransformation of MNP (40 µM) to MNPSO2 was evaluated after the inactivation of flavin-monooxygenase (FMO) system by heating and in the presence of metabolic inhibitors such as methimazole (MTZ) (FMO inhibitor) and piperonyl butoxide (PB) (cytochrome P450 inhibitor). MNP and MNPSO2. were incubated under anaerobic conditions during 3, 6 and 24 h in ruminal contents collected from untreated adult sheep and cattle. The partition of both molecules between the solid and fluid phases of ruminal content of both species was assessed. MNP and MNPSO2 concentrations were measured by HPLC .Results: MNP and MNPSO2 showed a high chemical stability without evident metabolism and/or degradation in ruminal contents of sheep and cattle. Both molecules were extensively bound (> 85%) to the solid material of ruminal content. Significant higher (p