Identification of metabolites of a substance P (Neurokinin 1 receptor) antagonist in rat hepatocytes and rat plasma
Author
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.-H.L.
Curtis, N.
Elliott, J.
Gerhard, U.
Locker, K.
Morrison, D.
Mortishire-Smith, R.
Thomas, S.
Watt, A.P.
Evans, D.C.
Attention
2299/8950
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.