Assessment of monepantel and monepantel sulphone gastrointestinal concentration profiles in sheep: relevance of the kinetics/efficacy relationship

Abstract

Monepantel (MNP) is a novel amino-acetonitrile derivative anthelmintic drug. Based on a distinctive mode of action, MNP is active against a variety of multidrug resistant gastrointestinal (GI) nematodes (Kaminsky et al. 2008). The plasma pharmacokinetics of MNP and its main sulphone metabolite (MNPSO2) has been described in sheep (Karadzovska et al., 2009). The anthelmintic efficacy greatly depends on the active drug concentrations attained at the sites of nematode location (Lanusse and Prichard, 1993). Thus, data on MNP concentration profiles reached in target tissues is needed to optimize its therapeutic use. The goal of the current study was to assess the relationship between the plasma disposition kinetics of MNP and MNPSO2 and their concentration profiles attained in GI tissues of parasite location in sheep. Twenty two healthy lambs received MNP (Zolvix®, Novartis) orally at 2.5 mg/kg. Blood samples were collected from six animals between 0 and 14 days post-treatment (plasma disposition study). Additionally, four lambs were sacrificed at 8, 24, 48 and 96 hours post-administration to measure the drug/metabolite concentrations at the mucosa and luminal contents from abomasum and duodenum. Drug concentrations were measured by HPLC. MNP concentrations in plasma were significantly lower compared to its sulphone metabolite. The peak plasma concentrations were 15.1 (MNP) and 61.3 ng/ml (MNPSO2). MNP and MNPSO2 levels measured in GI contents and mucosal tissue were considerably higher than those recovered in the bloodstream. At 24 hours post-treatment, mean MNP (3943 ng/ml) and MNPSO2 (204 ng/ml) concentrations in abomasal content were markedly higher than those recovered in plasma, which ranged between 10.8 (MNP) and 60.3 (MNPSO2) ng/ml. Although MNP is efficiently metabolized to MNPSO2 in the liver, the large concentration profiles of both anthelmintically active molecules recovered from the abomasum and small intestine may greatly contribute to the broad spectrum efficacy against GI nematodes.