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

(+/-)-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 (R)-HILIC) column using LC-MS and LC-MS2. 4-MMC was metabolised, yielding 17 metabolites. These metabolites were structurally characterised on the basis of accurate mass analyses and LC-MS2 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 beta-keto moiety. The bio-transformation 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(1/2)) for 4-MMC=61.9 min and for 4-TEMMC=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 (C) 2012 Elsevier B.V. All rights reserved.