Accumulation of monepantel and its sulphone derivative in tissues of nematode location in sheep: Pharmacokinetic support to its excellent nematodicidal activity.

LISCHITZ, A; BALLENT, M; VIRKEL, G ; SALLOVITZ, J; VIVIANI, P; LANUSSE, C

VETERINARY PARASITOLOGY

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2014

0304-4017

tThe amino-acetonitrile derivatives (AADs) are a new class of anthelmintic molecules activeagainst a wide range of sheep gastrointestinal (GI) nematodes including those that are resis-tant to other anthelmintic families. The plasma disposition of monepantel (MNP) has beenpreviously characterized in sheep. However, information on drug concentration profilesattained at tissues of parasite location is necessary to fully understand the pharmacologicalaction of this novel compound. The current work aimed to study the relationship betweenthe concentrations of MNP parent drug and its main metabolite monepantel sulphone(MNPSO2), measured in the bloodstream and in different GI tissues of parasite location insheep. Twenty two (22) uninfected healthy Romney Marsh lambs received MNP (Zolvix®,Novartis Animal Health) orally administered at 2.5 mg/kg. Blood samples were collectedfrom six animals between 0 and 14 days post-treatment to characterize the drug/metaboliteplasma disposition kinetics. Additionally, 16 lambs were sacrificed at 8, 24, 48 and 96 hpost-administration to assess the drug concentrations in the GI fluid contents and tissues.MNP and MNPSO2concentrations were determined by HPLC. MNP parent compound wasrapidly oxidized into MNPSO2. MNP systemic availability was significantly lower than thatobserved for MNPSO2. The peak plasma concentrations were 15.1 (MNP) and 61.4 ng/ml(MNPSO2). The MNPSO2to MNP plasma concentration profile ratio (values expressed inAUC) reached a value of 12. Markedly higher concentrations of MNP and MNPSO2weremeasured in both abomasal and duodenal fluid contents, and mucosal tissues comparedto those recovered from the bloodstream. A great MNP availability was measured in theabomasal content with concentration values ranging between 2000 and 4000 ng/g dur-ing the first 48 h post-treatment. Interestingly, the metabolite MNPSO2was also recoveredin abomasal content but its concentrations were significantly lower compared to MNP.The parent drug and its sulphone metabolite were detected in the different segments ofthe sheep intestine. MNPSO2concentrations in the different intestine sections sampledwere significantly higher compared to those measured in the abomasum. Although MNPis metabolized to MNPSO2in the liver, the large concentrations of both anthelminticallyactive molecules recovered during the first 48 h post-treatment from the abomasum andsmall intestine may greatly contribute to the well-established pharmacological activity ofMNP against GI nematodes