TY - JOUR
T1 - Identification of metabolites of a substance P (Neurokinin 1 receptor) antagonist in rat hepatocytes and rat plasma
AU - Hop, C.E.C.A.
AU - Wang, Y.
AU - Kumar, S.
AU - Elipe, M.V.S.
AU - Raab, C.E.
AU - Dean, D.C.
AU - Poon, G.K.
AU - Keohane, C.-A.
AU - Strauss, J.
AU - Chiu, S.-H.L.
AU - Curtis, N.
AU - Elliott, J.
AU - Gerhard, U.
AU - Locker, K.
AU - Morrison, D.
AU - Mortishire-Smith, R.
AU - Thomas, S.
AU - Watt, A.P.
AU - Evans, D.C.
N1 - MEDLINE® is the source for the MeSH terms of this document.
PY - 2002/1/1
Y1 - 2002/1/1
N2 - [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.
AB - [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.
UR - https://www.scopus.com/pages/publications/0036320875
U2 - 10.1124/dmd.30.8.937
DO - 10.1124/dmd.30.8.937
M3 - Article
AN - SCOPUS:0036320875
SN - 0090-9556
VL - 30
SP - 937
EP - 943
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
IS - 8
ER -