Characterization of Biliary Metabolites of the Potent 5-HT1D Receptor Antagonist, Elzasonan in Rats by HPLC/RAM/ESI/MS/MS

摘要

Routes of excretion and metabolite identification of CP-448,187 in rat bile following oral administration of a single dose of [~(14)C]-CP-448,187 at a free base equivalent of 8 mg/kg and 4 mg/kg for male and female rats, respectively, were studied. In addition to unchanged drug, a total of 6 metabolites were tentatively identified and accounted for 94.6 and 95.4percent of the total radioactivity extracted from bile in male and female rats, respectively. The major metabolites in both male and female rats were indeed the glucuronide conjugates of the hydroxylated N-desmethyl CP-448,187 and the hydroxylated CP-448,187 and accounted for approximately 22 and 51percent of the total radioactivity, respectively (average of male and female). Based on the structures of these metabolites, three major and two minor routes of metabolism of CP-44,187 were proposed. The major routes were due to N-demethylation, aromatic hydroxylation, and glucuronidation. The minor routes included: oxidation at the 5-position of the thiomorpholin-3-one ring and oxidation at the piperazine ring and subsequent rearrangement and ring closure to form the novel indole iminium ion metabolite.