C. Prakash et al., METABOLISM AND EXCRETION OF A NEW ANXIOLYTIC DRUG CANDIDATE, CP-93,393, IN HEALTHY MALE-VOLUNTEERS, Drug metabolism and disposition, 26(5), 1998, pp. 448-456
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.