title: Metabolic profile of mephedrone: Identification of nor-mephedrone conjugates with dicarboxylic acids as a new type of xenobiotic phase II metabolites.
abstract: Metabolic profile of mephedrone (4-methylmethcathinone, 4-MMC), a frequently abused recreational drug, was determined in rats in vivo. The urine of rats dosed with a subcutaneous bolus dose of 20mg 4-MMC/kg was analysed by LC/MS. Ten phase I and five phase II metabolites were identified by comparison of their retention times and MS(2) spectra with those of authentic reference standards and/or with the MS(2) spectra of previously identified metabolites. The main metabolic pathway was N-demethylation leading to normephedrone (4-methylcathinone, 4-MC) which was further conjugated with succinic, glutaric and adipic acid. Other phase I metabolic pathways included oxidation of the 4-methyl group, carbonyl reduction leading to dihydro-metabolites and ω-oxidation at the position 3'. Five of the metabolites detected, namely, 4-carboxynormephedrone (4-carboxycathinone, 4-CC), 4-carboxydihydronormephedrone (4-carboxynorephedrine, 4-CNE), hydroxytolyldihydro-normephedrone (4-hydroxymethylnorephedrine, 4-OH-MNE) and conjugates of 4-MC with glutaric and adipic acid, have not been reported as yet. The last two conjugates represent a novel, hitherto unexploited, type of phase II metabolites in mammals together with an analogous succinic acid conjugate of 4-MC identified by Pozo et al. (2015). These conjugates might be potentially of great importance in the metabolism of other psychoactive amines.
authors.affiliation: Department of Organic Chemistry, Faculty of Chemical Technology, University of Chemistry and Technology, Prague, Czech Republic. Electronic address: linharti@vscht.cz.
authors.forename: Igor
authors.initials: I
authors.lastname: Linhart
authors.affiliation: Department of Organic Chemistry, Faculty of Chemical Technology, University of Chemistry and Technology, Prague, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Himl
authors.affiliation: Institute of Forensic Medicine and Toxicology, 1st Faculty of Medicine, Charles University in Prague, Czech Republic.
authors.forename: Monika
authors.initials: M
authors.lastname: Židková
authors.affiliation: Institute of Forensic Medicine and Toxicology, 1st Faculty of Medicine, Charles University in Prague, Czech Republic.
authors.forename: Marie
authors.initials: M
authors.lastname: Balíková
authors.affiliation: National Institute of Mental Health, Klecany, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Lhotková
authors.affiliation: National Institute of Mental Health, Klecany, Czech Republic.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Páleníček
mesh_terms: D000272:Adipates / Q000378:metabolism; D000818:Animals; D002853:Chromatography, Liquid; D003998:Dicarboxylic Acids / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005977:Glutarates / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D055442:Metabolome; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D019802:Succinic Acid / Q000378:metabolism; D015262:Xenobiotics / Q000737:chemistry / Q000633:toxicity* / Q000652:urine
chemical_list: D000272:Adipates; D003998:Dicarboxylic Acids; D005977:Glutarates; D015262:Xenobiotics; D008694:Methamphetamine; C029900:adipic acid; C548233:mephedrone; D019802:Succinic Acid; C035736:glutaric acid
keywords: Designer drugs; Dicarboxylic acid conjugates; Mephedron metabolism