Metabolism, pharmacokinetics, and excretion of the substance P receptor antagonist CP-122,721 in humans: structural characterization of the novel major circulating metabolite 5-trifluoromethoxy salicylic acid by high-performance liquid chromatography-tandem mass spectrometry and NMR spectroscopy.

The metabolism, pharmacokinetics, and excretion of a potent and selective substance P receptor antagonist, CP-122,721 [(+)-(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzylamino)-2-phenylpiperidine], have been studied in six healthy male human subjects [four extensive metabolizers (EMs) and two poor metabolizers (PMs) of CYP2D6) following oral administration of a single 30-mg dose of [14C]CP-122,721. Approximately 84% of the administered radioactivity was recovered from the urine and feces of the subjects over a period of 312 h. Approximately 80% of the dose for EM subjects was recovered within 48 h. PM subjects, however, excreted only about 45% of the dose in 48 h and required the full 312 h to achieve nearly 80% recovery. Absorption of CP-122,721 was rapid in both extensive and poor metabolizers, as indicated by the rapid appearance of radioactivity in serum. The serum concentrations of total radioactivity were always much greater than those of unchanged drug indicating early formation of metabolites. The average CP-122,721 t1/2 was 6.7 h and 45.0 h for EM and PM subjects, respectively. The serum concentrations of CP-122,721 reached a peak of 7.4 and 69.8 ng/ml for extensive and poor metabolizers, respectively. 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, O-dealkylation of the trifluoromethoxy group, N-dealkylation, and oxidative deamination. In addition to the major human circulating metabolite 5-trifluoromethoxy salicylic acid (TFMSA), all other circulating metabolites of CP-122,721 were glucuronide conjugates of oxidized metabolites. TFMSA was identified using high pressure liquid chromatography/tandem mass spectrometry and NMR and mechanisms were proposed for its formation. There are no known circulating active metabolites of CP-122,721.