Investigation of the metabolism of monepantel in ovine hepatocytes by UHPLC/MS/MS

Abstract

Monepantel (MOP) belongs to a new class of anthelmintic drugs known as aminoacetonitrile derivatives. It was approved for use in veterinary practice in Czech Republic in 2011. So far, biotransformation and transport of MOP in target animals have been studied insufficiently, although the study of metabolic pathways of anthelmintics is very important for the efficacy of safety of therapy and evaluation of the risk of drug-drug interactions. The aim of this study was to identify MOP metabolites and to suggest the metabolic pathways of MOP in sheep. For this purpose, primary culture of ovine hepatocytes was used as a model in vitro system. After incubation, medium samples and homogenates of hepatocytes were extracted separately using solid-phase extraction. Analysis was performed using a hybrid quadrupole-time-of-flight analyzer with respect to high mass accuracy measurements in full scan and tandem mass spectra for the confirmation of an elemental composition. The obtained results revealed S-oxidation to sulfoxide and sulfone and arene hydroxylation as MOP phase I biotransformations. From phase II metabolites, MOP glucuronides, sulfates, and acetylcysteine conjugates were found. Based on the obtained results, a scheme of the metabolic pathway of MOP in sheep has been proposed.

Basic and clinical pharmacology contribution to extend anthelmintic molecules lifespan

“…As the persistence of monepantel sulphone is significantly longer than that of monepantel, this metabolite is the marker for tissue residue studies. Although the sulphone was the main metabolite detected in the bloodstream of sheep after monepantel administration, nine phase I and phase II metabolites were recovered after in vitro monepantel incubation in primary culture of ovine hepatocytes (Stuchlíková et al, 2013). Recently, ten monepantel metabolites were found in urine and eight monepantel metabolites were recovered in faeces (Stuchlíková et al, 2014).…”

Comparison of biotransformation and efficacy of aminoacetonitrile anthelmintics in vitro

“…The resultant aminoacetonitriles were finally converted to their amides by the reaction with 4-(trifluoromethoxy)benzoyl chloride (82-98% yield). [6] The structure and purity of prepared substances were tested using nuclear magnetic resonance spectrometry and ultrahighperformance liquid chromatography coupled with mass spectrometry (UHPLC-MS). [6] The structure and purity of prepared substances were tested using nuclear magnetic resonance spectrometry and ultrahighperformance liquid chromatography coupled with mass spectrometry (UHPLC-MS).…”

“…[6] Samples were evaporated to dryness using vacuum concentrator. After the attachment of hepatocytes, the medium was replaced with fresh serumfree one with AADs (10 μM in 3 mL of fresh medium).…”

“…[4] Although MOP is metabolized to MOP-sulfone in the liver, the large concentrations of both anthelmintically active molecules recovered during the first 48 h post-treatment from the abomasum and small intestine may greatly contribute to the well-established pharmacological activity of MOP against GI nematodes. [6,7] It is generally known that extensive drug biotransformation increases the risk of drug-drug interactions as well as inter-individual differences in drug pharmacokinetics. [6,7] It is generally known that extensive drug biotransformation increases the risk of drug-drug interactions as well as inter-individual differences in drug pharmacokinetics.…”

EVOLUTION IN CHEMOTHERAPY OF HUMAN AND ANIMAL HELMINTHIASES (review)

“…The most active metabolite is monepantel sulfone (81,82); this substance is effective in low doses (2.5-3.5 mg/kg) against a broad spectrum of gastro-intestinal helminths in larval and adult stages resistant to conventional anthelmintics (83). Interaction of monepantel with nematode-specific nAChR Hco-MPTL-1 leads to dysfunction of this receptor which paralyzes helminth's muscles (84,85).…”