Monepantel induces hepatic cytochromes p450 in sheep in vitro and in vivo

Abstract

Monepantel (MOP), a new amino-acetonitrile anthelmintic for the treatment and control of gastrointestinal nematode infections and associated diseases in sheep, is approved and marketed as oral solution under the trade name Zolvix® (Novartis Animal Health Inc., Switzerland). The effect of MOP on hepatic cytochromes P450 (CYP) has been investigated in sheep. In an in vivo experiment, castrated rams (9-months old) were treated with the recommended therapeutic dose of MOP. Non-treated animals represented the controls. After 24h, the animals were stunned and exsanguinated. Microsomal fractions and total RNA were prepared from liver homogenates. The activities towards alkyloxyresorufins, 7-methoxy-4-trifluoromethylcoumarin and midazolam were assayed and mRNAs of individual CYP isoforms were quantified. In an in vitro procedure, primary cultures of ovine hepatocytes were incubated with or without MOP (10μM) for 24h and then expression levels of individual CYP isoforms were analyzed. Results showed that MOP significantly increased all CYP-related activities and CYP3A24 mRNA in sheep. The induction effect of MOP on CYP3A was similar or even higher than those of dexamethasone and rifampicin, well-known CYP3A inducers. As CYP3A enzymes belongs to the most important biotransformation enzymes, their induction may have serious pharmacological and/or toxicological consequences. These facts should be taken into account when other drugs together with or after MOP (Zolvix®) are administered to sheep.