The New Anthelmintic Monepantel: Pattern of Distribution to Gastrointestinal Contents and Mucosal Tissues in Sheep

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

Congreso; 12th International Congress of the European Association for Veterinary Pharmacology and Toxicology.; 2015

EAVPT

Introduction: The amino-acetonitrile derivatives (AADs) are a new class of anthelmintics (Kaminsky et al. 2008) with activity against a wide range of gastrointestinal (GI) nematodes including those that are resistant to others antiparasitic drugs. The plasma disposition of monepantel (MNP) and its main metabolites monepantel sulphone (MNPSO2) was characterized in sheep (Karadzovska et al., 2009). However information on drug concentrations at target tissues is necessary to understand the pharmacological action of this compound. The current work aimed to study the relationship between MNP and MNPSO2 concentrations measured in plasma and in GI tissues of parasite location in sheep. Material and Methods: Twenty two (22) healthy Romney Marsh lambs were used following internationally accepted welfare guidelines. Lambs received MNP (Zolvix®, Novartis) orally administered at 2.5 mg/kg. Blood samples were collected from six animals between 0 and 14 days post-treatment to characterize the plasma disposition kinetics. Additionally, 16 lambs were sacrificed at 8, 24, 48 and 96 hours post-administration to study the drug concentrations at GI tissues. MNP and MNPSO2 concentrations in plasma and GI tissues were determined by HPLC. Results: MNP was rapidly oxidized to MNPSO2. MNP plasma concentrations were significantly lower than those observed for MNPSO2. The peak plasma concentrations were 15.1 (MNP) and 61.3 ng/ml (MNPSO2). The ratio between the systemic availability (AUC values) of MNPSO2 and MNP was 12. Markedly higher concentrations of MNP and MNPSO2 were measured in abomasal and duodenal contents and mucosal tissue compared to those recovered in the bloodstream. The mean MNP and MNPSO2 concentrations in abomasal contents at 24 hours post-treatment were 3943 and 204 ng/g respectively, whereas the mean plasma concentrations were 10.8 (MNP) and 60.3 (MNPSO2) ng/ml. The biliary secretion of MNPSO2 may contribute to its high concentration recovered in the duodenal content (557 ng/g at 48 h post-treatment). High concentrations of MNP and its metabolite were quantified in all the investigated mucosal tissues. Concentration profiles of both molecules in abomasal and duodenal mucosa reflected their plasma disposition. The concentrations for MNP and MNPSO2 in duodenal mucosa at 24 hours post-administration were 293 and 1018 ng/g, respectively. Conclusions: Although MNP is converted to MNPSO2 in the liver, the large concentrations of both compounds detected over the first 48 h post-treatment in the abomasum and small intestine (duodenum) may greatly contribute to the efficacy against the GI nematodes. Considering that the sulphone metabolite has shown in vitro activity equivalent to MNP, the high levels of MNPSO2 measured in the digestive tract, particularly at the mucosal tissue, may be also contribute to the potent nematodicidal activity of the new anthelmintic molecule. The pharmacological information provided here is relevant to achieve a long-standing sustainable use of this novel chemical tool for parasite control.