TY - JOUR T1 - Excretion, Metabolism and Pharmacokinetics of 1-(8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-YL)-4-(ethylamino)piperidine-4-carboxamide, CP-945,598, a Selective Cannabinoid Receptor Antagonist, in Healthy Male Volunteers JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.111.043273 SP - dmd.111.043273 AU - Zhuang Miao AU - Hao Sun AU - Jennifer Liras AU - Chandra Prakash Y1 - 2011/01/01 UR - http://dmd.aspetjournals.org/content/early/2011/12/20/dmd.111.043273.abstract N2 - 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 CB-1 receptor, was studied following 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 posdose. The mean total recovery of radioactivity was 60.1±12.8 from the urine and feces, with majority of dose excreted in the feces. The absorption of CP-945,598 in humans was slow with Tmax 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. Taken together, these data suggest that CP-945,598 is well absorbed and eliminated largely by CYP3A4/3A5-catalyzed metabolism. ER -