title: 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.
authors.affiliation: Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Stuchlíková
authors.forename: Robert
authors.initials: R
authors.lastname: Jirásko
authors.forename: Ivan
authors.initials: I
authors.lastname: Vokřál
authors.forename: Jiří
authors.initials: J
authors.lastname: Lamka
authors.forename: Marcel
authors.initials: M
authors.lastname: Spulák
authors.forename: Michal
authors.initials: M
authors.lastname: Holčapek
authors.forename: Barbora
authors.initials: B
authors.lastname: Szotáková
authors.forename: Hana
authors.initials: H
authors.lastname: Bártíková
authors.forename: Milan
authors.initials: M
authors.lastname: Pour
authors.forename: Lenka
authors.initials: L
authors.lastname: Skálová
mesh_terms: D000607:Aminoacetonitrile / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D000871:Anthelmintics / Q000378:metabolism*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D022781:Hepatocytes / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D012756:Sheep / Q000378:metabolism*; D052616:Solid Phase Extraction; D053719:Tandem Mass Spectrometry
chemical_list: D000871:Anthelmintics; D000607:Aminoacetonitrile; C533978:monepantel