| dc.identifier.citation | Hop , C E C A , Wang , Y , Kumar , S , Elipe , M V S , Raab , C E , Dean , D C , Poon , G K , Keohane , C-A , Strauss , J , Chiu , S-HL , Curtis , N , Elliott , J , Gerhard , U , Locker , K , Morrison , D , Mortishire-Smith , R , Thomas , S , Watt , A P & Evans , D C 2002 , ' Identification of metabolites of a substance P (Neurokinin 1 receptor) antagonist in rat hepatocytes and rat plasma ' , Drug Metabolism and Disposition , vol. 30 , no. 8 , pp. 937-943 . https://doi.org/10.1124/dmd.30.8.937 | |
| dc.description.abstract | [3R,5R,6S]-3-(2-cyclopropyloxy-5-trifluoromethoxyphenyl)-6-phenyl-1-oxa-7 -azaspiro[4.5]decane is a substance P (Neurokinin 1 receptor) antagonist. Substance P antagonists are proven in concept to have excellent potential for the treatment of major depression, and they allow superior and sustained protection from acute and delayed chemotherapy-induced emesis. The metabolism of this compound was investigated in rat hepatocytes, and circulating rat plasma metabolites were identified following oral and intravenous dosing. The turnover in rat hepatocytes within 4 h was about 30%, and the major metabolites were identified as two nitrones and a lactam associated with the piperidine ring. Although these metabolites were also observed in rat plasma, the major circulating metabolite was a keto acid following oxidative de-amination of the piperidine ring. Liquid chromatography/tandem mass spectrometry and nuclear magnetic resonance were used to confirm the structure of the latter metabolite. A mechanism leading to the formation of the keto acid metabolite has been suggested, and most intermediates were observed in rat plasma. | en |
