RT Journal Article SR Electronic T1 Metabolism and Excretion of a New Anxiolytic Drug Candidate, CP-93,393, in Healthy Male Volunteers JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 448 OP 456 VO 26 IS 5 A1 Chandra Prakash A1 Donghui Cui A1 James G. Baxter A1 G. Michael Bright A1 Jeffrey Miceli A1 Keith Wilner YR 1998 UL http://dmd.aspetjournals.org/content/26/5/448.abstract AB CP-93,393 [(7S,9aS)-1-(2-pyrimidin-2-yloctahydropyrido[1,2-a] pyrazin-7-ylmethyl)pyrrolidine-2,5-dione] is a new anxiolytic drug with highly selective serotonin 5-hydroxytryptamine 1A autoreceptor agonist, α2-adrenergic antagonist, and dopamine D2 agonist properties. The excretion, biotransformation, and pharmacokinetics of CP-93,393 were investigated in six healthy male volunteers after oral administration of a 5-mg dose of [14C]CP-93,393. The administered radioactivity was excreted predominantly in the urine. One week after administration of the dose, cumulative excretion amounted to 67.8 ± 2.5% in the urine and 22.0 ± 5.6% in the feces. In total, 89.8 ± 5.7% of the radioactive dose was recovered in urine and feces. Mean maximum plasma concentration values for unchanged CP-93,393 were 10.92 and 1.02 ng/ml for poor metabolizers (PMs) and extensive metabolizers (EMs) of dextromethorphan, respectively. AUC0–∞ values for unchanged CP-93,393 were also greater for PMs than for EMs, whereas the mean maximum plasma concentration and AUC0–∞ values for total radioactivity were similar for the two phenotypes. Less than 0.5% of the dose was excreted in urine as unchanged drug for both EMs and PMs, suggesting extensive metabolism of CP-93,393 in both phenotypes. Hydroxylation at the 5-position of the pyrimidine ring was identified as the main metabolic pathway. 5-Hydroxy-CP-93,393 (M-15) and its glucuronide and sulfate conjugates (M-7 and M-13, respectively) accounted for ∼51% of the administered dose in excreta of both PMs and EMs. Hydrolysis of the succinimide ring, in combination with 5-hydroxylation and/or conjugation or not, accounted for ∼9% of the dose. A novel metabolite, apparently resulting from oxidative degradation of the pyrimidine ring, was characterized as the amidine analog M-18. M-15 (47–62%), its sulfate conjugate (M-13, ∼9%), and the pyrimidine ring-cleaved product (M-18, 7–13%) were identified as the major circulating metabolites for both EMs and PMs. Therefore, CP-93,393 undergoes metabolism by three primary pathways, i.e. 1) aromatic hydroxylation followed by conjugation with glucuronic acid and sulfuric acid, 2) oxidative degradation of the pyrimidine ring, and 3) hydrolysis of the succinimide ring. The identified metabolites accounted for approximately 90, 91, and 92% of the total radioactivity present in urine, plasma, and feces, respectively. The major in vivo oxidative metabolites were also observed after in vitro incubations with human liver microsomes. The American Society for Pharmacology and Experimental Therapeutics