TY - JOUR 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 SP - 937 LP - 943 DO - 10.1124/dmd.30.8.937 VL - 30 IS - 8 AU - Cornelis E. C. A. Hop AU - Yanfeng Wang AU - Sanjeev Kumar AU - Maria Victoria Silva Elipe AU - Conrad E. Raab AU - Dennis C. Dean AU - Grace K. Poon AU - Carol-Ann Keohane AU - John Strauss AU - Shuet-Hing L. Chiu AU - Neil Curtis AU - Jason Elliott AU - Ute Gerhard AU - Karen Locker AU - Denise Morrison AU - Russell Mortishire-Smith AU - Steven Thomas AU - Alan P. Watt AU - David C. Evans Y1 - 2002/08/01 UR - http://dmd.aspetjournals.org/content/30/8/937.abstract 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. The American Society for Pharmacology and Experimental Therapeutics ER -