RT Journal Article
SR Electronic
T1 Identification of Metabolites of a Substance P (Neurokinin 1 Receptor) Antagonist in Rat Hepatocytes and Rat Plasma
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 937
OP 943
DO 10.1124/dmd.30.8.937
VO 30
IS 8
A1 Cornelis E. C. A. Hop
A1 Yanfeng Wang
A1 Sanjeev Kumar
A1 Maria Victoria Silva Elipe
A1 Conrad E. Raab
A1 Dennis C. Dean
A1 Grace K. Poon
A1 Carol-Ann Keohane
A1 John Strauss
A1 Shuet-Hing L. Chiu
A1 Neil Curtis
A1 Jason Elliott
A1 Ute Gerhard
A1 Karen Locker
A1 Denise Morrison
A1 Russell Mortishire-Smith
A1 Steven Thomas
A1 Alan P. Watt
A1 David C. Evans
YR 2002
UL http://dmd.aspetjournals.org/content/30/8/937.abstract
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. The American Society for Pharmacology and Experimental Therapeutics