Metabolism, pharmacokinetics and excretion of a potent tachykinin NKI receptor antagonist (CP-122,721) in rat: Characterization of a novel oxidative pathway

The metabolism, pharmacokinetics and excretion of a potent and selective substance P receptor antagonist, (+)-(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzlamino)-2-phenylpiperidine, CP-122,721, have been studied in rat following oral administration of a single dose of [C-14] CP-122,721. Total recovery of the administered dose was 84.1 +/- 1.1% for male rat and 80.9 +/- 2.7% for female rat. Approximately 81% of the administered radioactivity recovered in urine and faeces were excreted in the first 72h. Absorption of CP-122,721 was rapid in both male and female rat, as indicated by the rapid appearance of radioactivity in plasma. The plasma concentrations of total radioactivity were always much greater than unchanged drug, indicating early formation of metabolites. CP-122,721 t(1/2) was 3.1 and 2.2 h for male and female rat, respectively. The plasma concentrations of CP-122,721 reached a peak of 941 and 476 ng ml(-1) for male and female rat, respectively, at 0.5h post-dose. Based on AUC(0-tlast), only 1.5% of the circulating radioactivity was attributable to unchanged drug (average of male and female rats) and the balance, approximately 98.5% of the plasma radioactivity was due to metabolites. The major metabolic pathways of CP-122,721 were due to O-demethylation, aromatic hydroxylation and indirect glucuronidation. The minor metabolic pathways included aliphatic oxidation at the piperidine moiety and aliphatic oxidation at the benzylic position of the trifluoromethoxy anisole moiety. In addition, a novel oxidative metabolite resulting from ipso substitution by the oxygen atom and trifluoromethoxy elimination followed by glucuronide conjugation was also identified.