Identification of in vitro metabolites of the GABA_(A) receptor partial agonist ~(14)CCP-409,092 by using HPLC/RAM/ESI/MS/MS

摘要

The routes of metabolism of CP-409,092 in rat hepatocyte were identical to those observed in rat plasma and were due to hydroxylation(s) and oxidative deamination and subsequent oxidation In human hepatocyte, however, oxidative deamination of CP-409,092 and subsequent oxidation to form the acid metabolite was the only evident metabolic pathway. Human hepatocyte incubation with aminobenzotriazole, deprenyl, and clorgyline, probe inhibitors of P-450, MAO-B, and MAO-A, respectively, showed that CP-409,092 was metabolized to a large extent by MAO-A. In human mitochondria, three metabolites were identified and were due to oxidative deamination to form the aldehyde metabolite and subsequent oxidation and reduction to form the acid metabolite and alcohol metabolite, respectively. Human mitochondria incubation with beta-NAD and beta-NADH had a marked effect on the metabolic turnover of CP-409,092 and resulted in driving the reaction to form the corresponding acid and alcohol metabolite as the only major peak. The data in this study indicate that the enzyme MAO-A is the major enzyme responsible for the metabolism of CP-409,092 in man. The above results also suggest that using an in vitro preparation derived from human liver, one can predict that oxidative deamination of CP-409,092 and subsequent oxidation to form the acid metabolite would be the major metabolic pathway in man.