TY - JOUR T1 - Bioactivation Pathways of the CB1r Antagonist Rimonabant JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.111.039412 SP - dmd.111.039412 AU - Moa Andresen Bergstrom AU - Emre M Isin AU - Neal Castagnoli AU - Claire E Milne Y1 - 2011/01/01 UR - http://dmd.aspetjournals.org/content/early/2011/07/06/dmd.111.039412.abstract N2 - In the present work, the characterization of the biotransformation and bioactivation pathways of the cannabinoid receptor 1 antagonist rimonabant (Acomplia®) is described. Rimonabant was approved in Europe in 2006 for the treatment of obesity but was withdrawn in 2008 due to a significant drug-related risk of serious psychiatric disorders. The aim of the present work is to characterize the biotransformation and potential bioactivation pathways of rimonabant in vitro in human and rat liver microsomes. The observation of a major iminium ion metabolite led us to perform reactive metabolite trapping, covalent binding to proteins and time-dependent inhibition of cytochrome P450 3A4 studies. The major biotransformation pathways were oxidative dehydrogenation of the piperidinyl ring to an iminium ion, hydroxylation of the 3-position of the piperidinyl ring and cleavage of the amide linkage. In co-incubations with potassium cyanide, three cyanide adducts were detected. A high level of covalent binding of rimonabant in human liver microsomes was observed (920 pmol eq./mg protein). In co-incubations with potassium cyanide and methoxylamine, the covalent binding was reduced by ca 40% and 30%, respectively whereas GSH had no significant effect on covalent binding levels. Rimonabant was also found to inhibit cytochrome P450 3A4 irreversibly in a time dependent manner. In view of these findings it is noteworthy that, to date, no toxicity findings related to the formation of reactive metabolites from rimonabant have been reported. ER -