title: Elucidation of the Phase I and Phase II metabolic pathways of (±)-4'-methylmethcathinone (4-MMC) and (±)-4'-(trifluoromethyl)methcathinone (4-TFMMC) in rat liver hepatocytes using LC-MS and LC-MS².
abstract: (±)-4'-Methylmethcathinone hydrochloride [(±)-mephedrone, 4-MMC] is a synthetic "legal high", with a classical cathinone structure similar to methcathinone. In this study, the in vitro metabolism of 4-MMC was investigated in Sprague-Dawley rat hepatocytes to characterise the associated Phase I and II metabolites. 4-MMC was incubated with rat liver hepatocytes, and the reaction mixture was analysed on a zwitterionic hydrophilic interaction (ZIC-HILIC) column using LC-MS and LC-MS(2). 4-MMC was metabolised, yielding 17 metabolites. These metabolites were structurally characterised on the basis of accurate mass analyses and LC-MS(2) fragmentation patterns and the major metabolic routes for 4-MMC determined to be via (i) oxidation of the 4'-methyl group and (ii) reduction of the β-keto moiety. The biotransformation of a modified 4'-trifluoromethyl- derivative (4-TFMMC) has also been studied and shows significant differences in its metabolism compared to 4-MMC. Key pharmacokinetic parameters for both drugs have been calculated [biological half-lives (t(½)) for 4-MMC=61.9 min and for 4-TFMMC=203.8 min] and this data may aid in the understanding of in vivo metabolism and the likely pharmacokinetic effects of chemical/structural modifications within this class of controlled substances.
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.
authors.forename: Osama I G
authors.initials: OI
authors.lastname: Khreit
authors.forename: M Helen
authors.initials: MH
authors.lastname: Grant
authors.forename: Tong
authors.initials: T
authors.lastname: Zhang
authors.forename: Catherine
authors.initials: C
authors.lastname: Henderson
authors.forename: David G
authors.initials: DG
authors.lastname: Watson
authors.forename: Oliver B
authors.initials: OB
authors.lastname: Sutcliffe
mesh_terms: D000818:Animals; D001711:Biotransformation; D002470:Cell Survival; D002853:Chromatography, Liquid / Q000379:methods; D022781:Hepatocytes / Q000737:chemistry / Q000378:metabolism*; D008099:Liver / Q000737:chemistry* / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D050216:Metabolic Detoxication, Phase I; D050217:Metabolic Detoxication, Phase II; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D008694:Methamphetamine; C548233:mephedrone