title: Characterizing metabolites and potential metabolic pathways for the novel psychoactive substance methoxetamine.
abstract: The classic approach of controlled volunteer studies to study drug metabolism is difficult or impossible to undertake for novel psychoactive substances (NPS), as there is generally very limited information available to allow appropriate dose finding and safety. A viable and powerful alternative is the identification and characterization of phase I and II metabolites of such drugs by examining the concordance of data gathered from analysis of microsomal incubates with that from analysis of specimens collected from individuals with analytically confirmed use of NPS. Liquid chromatography-high resolution mass spectrometry provides the ability to reliably identify such metabolites. We used this technique here to study the metabolism of the ketamine analogue methoxetamine. A large number of metabolites were identified in the in vitro studies including normethoxetamine, O-desmethylmethoxetamine, dihydromethoxetamine, dehydromethoxetamine and several structural isomers of hydroxymethoxetamine and hydroxynormethoxetamine. pH dependent liquid-liquid extraction was used to discriminate phenolic from alcoholic metabolites. Phase II glucuronide conjugates included those of O-desmethylmethoxetamine, O-desmethylnormethoxetamine and O-desmethylhydroxymethoxetamine. The majority of these phase I and II metabolites were confirmed to be present in urine collected from three individuals presenting with acute methoxetamine toxicity.
authors.affiliation: Drug Control Centre, Analytical and Environmental Sciences Division, School of Biomedical Sciences, King's College London, 150 Stamford Street, London, SE1 9NH, UK.
authors.forename: E L
authors.initials: EL
authors.lastname: Menzies
authors.forename: S C
authors.initials: SC
authors.lastname: Hudson
authors.forename: P I
authors.initials: PI
authors.lastname: Dargan
authors.forename: M C
authors.initials: MC
authors.lastname: Parkin
authors.forename: D M
authors.initials: DM
authors.lastname: Wood
authors.forename: A T
authors.initials: AT
authors.lastname: Kicman
mesh_terms: D002853:Chromatography, Liquid / Q000379:methods*; D003512:Cyclohexanones / Q000378:metabolism*; D003514:Cyclohexylamines / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D013287:Illicit Drugs / Q000378:metabolism*; D059625:Liquid-Liquid Extraction; D013058:Mass Spectrometry / Q000379:methods*
chemical_list: D003512:Cyclohexanones; D003514:Cyclohexylamines; D013287:Illicit Drugs; C569113:2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone
keywords: high resolution mass spectrometry; metabolism; methoxetamine; new psychoactive substance