Metabolism and excretion of a new antianxiety drug candidate, CP-93,393, in cynomolgus monkeys: identification of the novel pyrimidine ring cleaved metabolites.
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-infinity) 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, beta-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, approximately 34%), and the pyrimidine ring cleaved product (M18, approximately 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.
Prakash
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Department of Drug Metabolism, Central Research Division, Pfizer Inc., Groton, CT 06340, USA.
Cui
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D058669:Adrenergic alpha-2 Receptor Antagonists; D000818:Animals; D014151:Anti-Anxiety Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001646:Bile / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D011719:Pyrazines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011743:Pyrimidines / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D013388:Succinimides / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D058669:Adrenergic alpha-2 Receptor Antagonists; D014151:Anti-Anxiety Agents; C109842:CP 93393; D011719:Pyrazines; D011743:Pyrimidines; D017366:Serotonin Receptor Agonists; D013388:Succinimides