title: Monepantel induces hepatic cytochromes p450 in sheep in vitro and in vivo.
abstract: Monepantel (MOP), a new amino-acetonitrile anthelmintic for the treatment and control of gastrointestinal nematode infections and associated diseases in sheep, is approved and marketed as oral solution under the trade name Zolvix® (Novartis Animal Health Inc., Switzerland). The effect of MOP on hepatic cytochromes P450 (CYP) has been investigated in sheep. In an in vivo experiment, castrated rams (9-months old) were treated with the recommended therapeutic dose of MOP. Non-treated animals represented the controls. After 24 h, the animals were stunned and exsanguinated. Microsomal fractions and total RNA were prepared from liver homogenates. The activities towards alkyloxyresorufins, 7-methoxy-4-trifluoromethylcoumarin and midazolam were assayed and mRNAs of individual CYP isoforms were quantified. In an in vitro procedure, primary cultures of ovine hepatocytes were incubated with or without MOP (10 μM) for 24 h and then expression levels of individual CYP isoforms were analyzed. Results showed that MOP significantly increased all CYP-related activities and CYP3A24 mRNA in sheep. The induction effect of MOP on CYP3A was similar or even higher than those of dexamethasone and rifampicin, well-known CYP3A inducers. As CYP3A enzymes belongs to the most important biotransformation enzymes, their induction may have serious pharmacological and/or toxicological consequences. These facts should be taken into account when other drugs together with or after MOP (Zolvix®) are administered to sheep.
authors.affiliation: Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Stuchlíková
authors.affiliation: Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Matoušková
authors.affiliation: Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Bártíková
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Ivan
authors.initials: I
authors.lastname: Vokřál
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Lamka
authors.affiliation: Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Tereza
authors.initials: T
authors.lastname: Štolcová
authors.affiliation: Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Pětníková
authors.affiliation: Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Barbora
authors.initials: B
authors.lastname: Szotáková
authors.affiliation: Department of Biophysics and Physical Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Vladimír
authors.initials: V
authors.lastname: Kubíček
authors.affiliation: Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: skaloval@faf.cuni.cz.
authors.forename: Lenka
authors.initials: L
authors.lastname: Skálová
mesh_terms: D000607:Aminoacetonitrile / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012756:Sheep
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; D000607:Aminoacetonitrile; C533978:monepantel; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A
keywords: Anthelmintics; CYP3A; CYP3A24; Drug–drug interactions; Zolvix