Excretion, Metabolism, and Pharmacokinetics of CP-945,598, a Selective Cannabinoid Receptor Antagonist, in Rats, Mice, and Dogs

Abstract

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.

Excretion, Metabolism, and Pharmacokinetics of 1-(8-(2-Chlorophenyl)-9-(4-Chlorophenyl)-9H-Purin-6-yl)-4-(Ethylamino)Piperidine-4-Carboxamide, a Selective Cannabinoid Receptor Antagonist, in Healthy Male Volunteers

“…A major portion of the administered radioactive dose was eliminated via the fecal (ϳ46%) route, and urinary elimination accounted for only ϳ14% of the dose. These results are consistent with data from the preclinical toxicology species, in which CP-945,598 was eliminated mainly in feces also (Miao et al, 2011). However, the total recovery of administered radioactivity in humans was low (60%), in contrast to preclinical species in which the radioactive dose was quantitatively recovered (Ͼ97%).…”

“…The synthetic reference compound standards 4-amino-1-(8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl)piperidine-4-carboxamide (CE-156,706, M1), 4-amino-1-(8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl)piperidine-4-carboxylic acid 764,M2), and 1-(8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl)piperidin-4-one (CE-127,773, M5) were synthesized as described previously ( Fig. 1) (Miao et al, 2011).…”

“…Serum concentrations of CP-945,598 and CE-156,706 (M1) were determined at PPD Development (Richmond, VA) using a validated LC-MS/MS assay (Miao et al, 2011). Pharmacokinetic parameters were determined using the WinNonlin version 3.2 program (Pharsight, Mountain View, CA).…”

“…The major route of excretion in all three species was via the biliary-fecal route. CP-945,598 is metabolized extensively in all three species, because no unchanged parent compound was detected in the urine across species and metabolism was the primary route of clearance (Miao et al, 2011). The primary metabolic pathway was due to the oxidative N-deethylation to form an N-desethyl metabolite (M1), which was then subsequently metabolized to numerous novel and unusual metabolites.…”

Gender-Dependent Pharmacokinetics of Veratramine in Rats: In Vivo and In Vitro Evidence

“…Mechanisms of gender-dependent pharmacokinetics may include differences in cardiac output, body composition, body weight, hormonal status, and metabolism between genders (57,58). One factor commonly known to contribute to gender-related metabolism, the major reason for gender difference on pharmacokinetic behavior, is the differential expression of drug-processing enzymes including phase I and phase II metabolic enzymes (P450s, sulfotransferases, glutathione transferases, and UDP-glucuronosyltransferases) (59).…”