METABOLISM AND EXCRETION OF A NEW ANXIOLYTIC DRUG CANDIDATE, CP-93,393, IN HEALTHY MALE-VOLUNTEERS

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 B-hydroxytryptamine 1A autoreceptor agonist, alpha (2)-adrenergic antagonist, and dopamine D2 agonist properties. The exc retion, biotransformation, and pharmacokinetics of CP-93,393 were inve stigated in six healthy male volunteers after oral administration of a 5-mg dose of [C-14]CP-93,393. The administered radioactivity was excr eted 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 concentrat ion values for unchanged CP-93,393 were 10.92 and 1.02 ng/ml for poor metabolizers (PMs) and extensive metabolizers (EMs) of dextromethorpha n, respectively. AUC(0-infinity), values for unchanged CP-93,393 were also greater for PMs than for EMs, whereas the mean maximum plasma con centration and AUC(0-infinity) values for total radioactivity were sim ilar for the two phenotypes. Less than 0.5% of the dose was excreted i n urine as unchanged drug for both EMs and PMs, suggesting extensive m etabolism of CP-93,393 in both phenotypes. Hydroxylation at the 5-posi tion of the pyrimidine ring was identified as the main metabolic pathw ay. 5-Hydroxy-CP-93,393 (M-15) and its glucuronide and sulfate conjuga tes (M-7 and M-13, respectively) accounted for similar to 51% of the a dministered dose in excreta of both PMs and EMs. Hydrolysis of the suc cinimide ring, in combination with 5-hydroxylation and/or conjugation or not, accounted for similar to 9% of the dose. A novel metabolite, a pparently resulting from oxidative degradation of the pyrimidine ring, was characterized as the amidine analog M-18, M-15 (47-62%), its sulf ate conjugate (M-13, similar to 9%), and the pyrimidine ring-cleaved p roduct (M-18, 7-13%) were identified as the major circulating metaboli tes for both EMs and PMs. Therefore, CP-93,393 undergoes metabolism by three primary pathways, be. 1) aromatic hydroxylation followed by con jugation with glucuronic acid and sulfuric acid, 2) oxidative degradat ion 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, resp ectively. The major in vivo oxidative metabolites were also observed a fter in vitro incubations with human liver microsomes.