Abstract

The disposition of 1-(8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H- purin-6-yl)-4-(ethylamino)-piperidine-4-carboxamide (CP-945,598), an orally active antagonist of the cannabinoid CB1 receptor, was studied after a single 25-mg oral dose of [¹⁴C]CP-945,598 to healthy human subjects. Serial blood samples and complete urine and feces were collected up to 672 h after dose. The mean total recovery of radioactivity was 60.1 ± 12.8 from the urine and feces, with the majority of the dose excreted in the feces. The absorption of CP-945,598 in humans was slow with T_max at 6 h. Less than 2% of the dose was recovered as unchanged drug in the combined excreta, suggesting that CP-945,598 is extensively metabolized. The primary metabolic pathway of CP-945,598 involved N-de-ethylation to form an N-desethyl metabolite (M1), which was then subsequently metabolized by amide hydrolysis (M2), N-hydroxylation (M3), piperidine ring hydroxylation (M6), and ribose conjugation (M9). M3 was further metabolized to oxime (M4) and keto (M5) metabolites. M1, M4, and M5 were the major circulating metabolites, with AUC_(0–48) values 4.7-, 1.5-, and 1.1-fold greater than that of CP-945,598. M1, M2, and M9 accounted for 5.6, 33.6, and 6.30% of the dose, respectively, in excreta. The results from in vitro experiments with recombinant isoforms suggested that the oxidative metabolism of CP-945,598 to M1 is catalyzed primarily by CYP3A4/3A5. The molecular docking study showed that the N-ethyl moiety of CP-945,598 can access to the heme iron-oxo of CYP3A4 in an energetically favored orientation. Together, these data suggest that CP-945,598 is well absorbed and eliminated largely by CYP3A4/3A5-catalyzed metabolism.