Identification of metabolites of a substance P (Neurokinin 1 receptor) antagonist in rat hepatocytes and rat plasma

C.E.C.A. Hop, Y. Wang, S. Kumar, M.V.S. Elipe, C.E. Raab, D.C. Dean, G.K. Poon, C.-A. Keohane, J. Strauss, S.-H.L. Chiu, N. Curtis, J. Elliott, U. Gerhard, K. Locker, D. Morrison, R. Mortishire-Smith, S. Thomas, A.P. Watt, D.C. Evans

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    10 Citations (Scopus)


    [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.
    Original languageEnglish
    Pages (from-to)937-943
    Number of pages7
    JournalDrug Metabolism and Disposition
    Issue number8
    Publication statusPublished - 1 Jan 2002


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