Characterization of in vivo Metabolites of the Potent 5-HT1D Receptor Antagonist CP-448,187 in Sprague-Dawley Rats by HPLC/RAM/ESI/MS/MS

摘要

CP-448,187 was extensively metabolized in rat and only a very small amount of unchanged drug was found in feces. Total recovery of radioactivity was approximately 98.0percent and approx100percent for male and female rats, respectively. The majority of the administered dose (97percent) was recovered within 72 hours. The major routes of metabolism were due to N-dealkylation of the methyl group attached to the piperazinyl nitrogen and aromatic hydroxylation(s) of the benzylidene moiety. The minor routes included: N-oxidation at the piperazine ring, epoxidation and subsequent hydrolysis, oxidation at the 5-position of the thiomorpholin-3-one ring, oxidation at the piperazine ring and subsequent rearrangement and ring closure to form a pyrazino-indol iminium ion meatbolite, oxidation at the piperazine ring and subsequent ring opening with N-dearylation of the dichloro phenyl moiety and scission of the thiomorpholin-3-one ring. The major components of drug related material in the excreta was in the feces and were tentatively identified as the desmethyl (M 9) and hydroxylated desmetyl (M 4) metabolites (approx=36.0percent and 17.0percent of the administered dose, respectively).