title: Mass spectrometric evaluation of mephedrone in vivo human metabolism: identification of phase I and phase II metabolites, including a novel succinyl conjugate.
abstract: In recent years, many new designer drugs have emerged, including the group of cathinone derivatives. One frequently occurring drug is mephedrone; although mephedrone was originally considered as a "legal high" product, it is currently banned in most Western countries. Despite the banning, abuse of the drug and seizures are continuously reported. Although the metabolism of mephedrone has been studied in rats or in vitro using human liver microsomes, to the best of our knowledge, no dedicated study with human volunteers has been performed for studying the in vivo metabolism of mephedrone in humans. Therefore, the aim of this study was to establish the actual human metabolism of mephedrone and to compare it with other models. For this purpose, urine samples of two healthy volunteers, who ingested 200 mg mephedrone orally, were taken before administration and 4 hours after substance intake. The discovery and identification of the phase I and phase II metabolites of mephedrone were based on ultra-high-performance liquid chromatography coupled to hybrid quadrupole time-of-flight mass spectrometry, operating in the so-called MS(E) mode. Six phase I metabolites and four phase II metabolites were identified, four of them not previously reported in the literature. The structure of four of the detected metabolites was confirmed by synthesis of the suggested compounds. Remarkably, a mephedrone metabolite conjugated with succinic acid has been identified and confirmed by synthesis. According to the reviewed literature, this is the first time that this type of conjugate is reported for human metabolism.
authors.affiliation: Bioanalysis Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Hospital del Mar Medical Research Institute, Barcelona, Spain (O.J.P.); Research Institute for Pesticides and Water, University Jaume I, Castellón, Spain (M.I., J.V.S., F.H.); Human Pharmacology and Clinical Neurosciences Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Hospital del Mar Medical Research Institute, Universitat Autònoma de Barcelona and Universitat Pompeu Fabra, Barcelona, Spain (J.L.-B., M.F., E.P., R.d.l.T.); and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom (J.L.-B.).
authors.forename: Óscar J
authors.initials: ÓJ
authors.lastname: Pozo
authors.affiliation: Bioanalysis Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Hospital del Mar Medical Research Institute, Barcelona, Spain (O.J.P.); Research Institute for Pesticides and Water, University Jaume I, Castellón, Spain (M.I., J.V.S., F.H.); Human Pharmacology and Clinical Neurosciences Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Hospital del Mar Medical Research Institute, Universitat Autònoma de Barcelona and Universitat Pompeu Fabra, Barcelona, Spain (J.L.-B., M.F., E.P., R.d.l.T.); and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom (J.L.-B.) ibanezm@uji.es.
authors.forename: María
authors.initials: M
authors.lastname: Ibáñez
authors.affiliation: Bioanalysis Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Hospital del Mar Medical Research Institute, Barcelona, Spain (O.J.P.); Research Institute for Pesticides and Water, University Jaume I, Castellón, Spain (M.I., J.V.S., F.H.); Human Pharmacology and Clinical Neurosciences Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Hospital del Mar Medical Research Institute, Universitat Autònoma de Barcelona and Universitat Pompeu Fabra, Barcelona, Spain (J.L.-B., M.F., E.P., R.d.l.T.); and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom (J.L.-B.).
authors.forename: Juan V
authors.initials: JV
authors.lastname: Sancho
authors.affiliation: Bioanalysis Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Hospital del Mar Medical Research Institute, Barcelona, Spain (O.J.P.); Research Institute for Pesticides and Water, University Jaume I, Castellón, Spain (M.I., J.V.S., F.H.); Human Pharmacology and Clinical Neurosciences Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Hospital del Mar Medical Research Institute, Universitat Autònoma de Barcelona and Universitat Pompeu Fabra, Barcelona, Spain (J.L.-B., M.F., E.P., R.d.l.T.); and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom (J.L.-B.).
authors.forename: Julio
authors.initials: J
authors.lastname: Lahoz-Beneytez
authors.affiliation: Bioanalysis Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Hospital del Mar Medical Research Institute, Barcelona, Spain (O.J.P.); Research Institute for Pesticides and Water, University Jaume I, Castellón, Spain (M.I., J.V.S., F.H.); Human Pharmacology and Clinical Neurosciences Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Hospital del Mar Medical Research Institute, Universitat Autònoma de Barcelona and Universitat Pompeu Fabra, Barcelona, Spain (J.L.-B., M.F., E.P., R.d.l.T.); and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom (J.L.-B.).
authors.forename: Magí
authors.initials: M
authors.lastname: Farré
authors.affiliation: Bioanalysis Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Hospital del Mar Medical Research Institute, Barcelona, Spain (O.J.P.); Research Institute for Pesticides and Water, University Jaume I, Castellón, Spain (M.I., J.V.S., F.H.); Human Pharmacology and Clinical Neurosciences Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Hospital del Mar Medical Research Institute, Universitat Autònoma de Barcelona and Universitat Pompeu Fabra, Barcelona, Spain (J.L.-B., M.F., E.P., R.d.l.T.); and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom (J.L.-B.).
authors.forename: Esther
authors.initials: E
authors.lastname: Papaseit
authors.affiliation: Bioanalysis Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Hospital del Mar Medical Research Institute, Barcelona, Spain (O.J.P.); Research Institute for Pesticides and Water, University Jaume I, Castellón, Spain (M.I., J.V.S., F.H.); Human Pharmacology and Clinical Neurosciences Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Hospital del Mar Medical Research Institute, Universitat Autònoma de Barcelona and Universitat Pompeu Fabra, Barcelona, Spain (J.L.-B., M.F., E.P., R.d.l.T.); and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom (J.L.-B.).
authors.forename: Rafael
authors.initials: R
authors.lastname: de la Torre
authors.affiliation: Bioanalysis Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Hospital del Mar Medical Research Institute, Barcelona, Spain (O.J.P.); Research Institute for Pesticides and Water, University Jaume I, Castellón, Spain (M.I., J.V.S., F.H.); Human Pharmacology and Clinical Neurosciences Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Hospital del Mar Medical Research Institute, Universitat Autònoma de Barcelona and Universitat Pompeu Fabra, Barcelona, Spain (J.L.-B., M.F., E.P., R.d.l.T.); and Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom (J.L.-B.).
authors.forename: Félix
authors.initials: F
authors.lastname: Hernández
mesh_terms: D000328:Adult; D002851:Chromatography, High Pressure Liquid; D015198:Designer Drugs / Q000032:analysis / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D008297:Male; D050216:Metabolic Detoxication, Phase I; D050217:Metabolic Detoxication, Phase II; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity / Q000652:urine; D015394:Molecular Structure; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry; D066007:Toxicokinetics
chemical_list: D015198:Designer Drugs; D008694:Methamphetamine; C548233:mephedrone