title: Excretion, metabolism, and pharmacokinetics of CP-945,598, a selective cannabinoid receptor antagonist, in rats, mice, and dogs.
abstract: 1-(8-(2-Chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl)-4-(ethylamino)piperidine-4-carboxamide (CP-945,598) is an orally active antagonist of the cannabinoid CB-1 receptor that progressed into phase 3 human clinical trials for the treatment of obesity. In this study, we investigated the metabolic fate and disposition of CP-945,598 in rats, Tg-RasH2 mice, and dogs after oral administration of a single dose of [(14)C]CP-945,598. Total mean recoveries of the radioactive dose were 97.7, 97.8, and 99.3% from mice, rats, and dogs, respectively. The major route of excretion in all three species was via the feces, but on the basis of separate studies in bile duct-cannulated rats and dogs, this probably reflects excretion in bile rather than incomplete absorption. CP-945,598 underwent extensive metabolism in all three species, because no unchanged parent compound was detected in the urine across species. The primary metabolic pathway of CP-945,598 involved N-deethylation to form an N-desethyl metabolite (M1). M1 was subsequently metabolized by amide hydrolysis, oxidation, and ribose conjugation to numerous novel and unusual metabolites. The major circulating and excretory metabolites were species-dependent; however, several common metabolites were observed in more than one species. In addition to parent compound, M1, M3, M4, and M5 in rats, M1, M3, and M4 in mice, and M1 and M2 in dogs were identified as the major circulating metabolites. Gender-related differences were also apparent in the quantitative and qualitative nature of the metabolites in rats. An unprecedented metabolite, M4, formed by deamidation of M1 or M3 (N-hydroxy-M1), but not by decarboxylation of M2, was identified in all species. M4 was nonenzymatically converted to M5.
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism Department, Pfizer Global Research and Development, Groton, CT 06340, USA. zhuangmiao@ct.metrocast.net
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Miao
authors.forename: Dennis O
authors.initials: DO
authors.lastname: Scott
authors.forename: David A
authors.initials: DA
authors.lastname: Griffith
authors.forename: Robert
authors.initials: R
authors.lastname: Day
authors.forename: Chandra
authors.initials: C
authors.lastname: Prakash
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005243:Feces; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011687:Purines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D053719:Tandem Mass Spectrometry
chemical_list: C535235:1-(9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl)-4-ethylaminopiperidine-4-carboxylic acid amide; D010880:Piperidines; D011687:Purines; D043884:Receptor, Cannabinoid, CB1