Metabolism And Excretion Of [C-14]Taranabant, A Cannabinoid-1 Inverse Agonist, In Humans

1. Taranabant (N-[(15,25)-3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide or MK-0364) is an orally active inverse agonist of the cannabinoid 1 (CB-1) receptor that was under development for the management of obesity. The metabolism and excretion of taranabant were investigated following a single oral dose of 5 mg/201 mu Ci [C-14] taranabant to six healthy male subjects. The overall excretion recovery of the administered radioactivity was nearly quantitative (similar to 92%), with the majority of the dose (similar to 87%) excreted into faeces and a much smaller fraction (similar to 5%) into urine.2. Taranabant was absorbed rapidly, with C-max of radioactivity attained at 1-2-h postdose. The parent compound and its monohydroxylated metabolite, M1, were the major radioactive components circulating in plasma and comprised similar to 12-24% and 33-42%, respectively, of the plasma radioactivity for up to 48 h. A second monohydroxylated metabolite, designated as M1 a, represented similar to 10-12% of the radioactivity in the 2- and 8-h postdose plasma profiles.3. Metabolite profiles of the faeces samples consisted mainly of the (unabsorbed) parent compound and multiple diastereomeric carboxylic acid derivatives derived from oxidation of the geminal methyl group of the parent compound and of the hydroxylated metabolite/s. These data suggest that, similar to rats and monkeys, taranabant is primarily eliminated in humans via oxidative metabolism and excretion of metabolites via the biliary/faecal route.