TY - JOUR T1 - Metabolism and Excretion of a New Antianxiety Drug Candidate, CP-93,393, in Cynomolgus Monkeys JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1395 LP - 1406 VL - 25 IS - 12 AU - Chandra Prakash AU - Donghui Cui Y1 - 1997/12/01 UR - http://dmd.aspetjournals.org/content/25/12/1395.abstract N2 - The metabolism and excretion of a new anxiolytic/antidepressant drug candidate, CP-93,393, {(7S,9aS)-1-(2-pyrimidin-2-yl-octahydro-pyrido[1,2-a]-pyrazin-7-yl-methyl)-pyrrolidine-2,5-dione} were investigated in cynomolgus monkeys after oral administration of a single 5 mg/kg dose of 14C-CP-93,393. Urine, bile, feces, and blood samples were collected and assayed for total radioactivity, parent drug, and metabolites. Total recovery of the administered dose after 6 days was 80% with the majority recovered during the first 48 hr. An average of 69% of the total radioactivity was recovered in urine, 4% in bile, and 7% in feces. Mean Cmax and AUC(0-∞)values for the unchanged CP-93,393 were 143.2 ng/ml and 497.7 ng·hr/ml, respectively, in the male monkeys and 17.2 ng/ml and 13.7 ng·hr/ml, respectively, in the female monkeys. HPLC analysis of urine, bile, feces, and plasma from both male and female monkeys indicated extensive metabolism of CP-93,393 to several metabolites. The identification of metabolites was achieved by chemical derivatization, β-glucuronidase/sulfatase treatment, and by LC/MS/MS, and the quantity of each metabolite was determined by radioactivity detector. CP-93,393 undergoes metabolism by three primary pathways, aromatic hydroxylation, oxidative degradation of the pyrimidine ring, and hydrolysis of the succinimide ring followed by a variety of secondary pathways, such as oxidation, methylation, and conjugation with glucuronic acid and sulfuric acid. The major metabolites, oxidation on the pyrimidine ring to form 5-OH-CP-93,393 (M15) followed by glucuronide and sulfate conjugation (M7 and M13), accounted for 35–45% of the dose in excreta. Two metabolites (M25 and M26) were formed by further oxidation of M15 followed by methylation of the resulting catechol intermediate presumably by catechol-O-methyl transferase. A novel metabolic pathway, resulting in the cleavage of the pyrimidine ring, was also identified. The metabolites (M18, M20, and M21) observed from this pathway accounted for 8–15% of the dose. Aliphatic hydroxylation of the succinimide ring was a very minor pathway in monkey. 5-Hydroxy-CP-93,393 (M15, 37–49%), its sulfate and glucuronide conjugates (M7 and M13, ∼34%), and the pyrimidine ring cleaved product (M18, ∼8%) were the major metabolites in monkey plasma. The identified metabolites accounted for approximately 90, 93, 97, and 92% of the total radioactivity present in urine, bile, plasma, and feces, respectively. The major in vivo oxidative metabolites were also observed after in vitro incubations with monkey liver microsomes. The American Society for Pharmacology and Experimental Therapeutics ER -