Identification of metabolites of a substance P (neurokinin 1 receptor) antagonist in rat hepatocytes and rat plasma.
[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.
Department of Drug Metabolism, Merck Research Laboratories, Rahway, New Jersey, USA. hopce@groton.pfizer.com
Cornelis E C A
CE
Hop
Yanfeng
Y
Wang
Sanjeev
S
Kumar
Maria Victoria Silva
MV
Elipe
Conrad E
CE
Raab
Dennis C
DC
Dean
Grace K
GK
Poon
Carol-Ann
CA
Keohane
John
J
Strauss
Shuet-Hing L
SH
Chiu
Neil
N
Curtis
Jason
J
Elliott
Ute
U
Gerhard
Karen
K
Locker
Denise
D
Morrison
Russell
R
Mortishire-Smith
Steven
S
Thomas
Alan P
AP
Watt
David C
DC
Evans
D000284:Administration, Oral; D000818:Animals; D001372:Aza Compounds / Q000097:blood* / Q000378:metabolism* / Q000494:pharmacology; D002853:Chromatography, Liquid; D022781:Hepatocytes / Q000378:metabolism*; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007651:Keto Acids / Q000097:blood; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D064729:Neurokinin-1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000097:blood* / Q000378:metabolism* / Q000494:pharmacology; D013373:Substance P / Q000037:antagonists & inhibitors*
C470509:3-(2-cyclopropyloxy-5-trifluoromethoxyphenyl)-6-phenyl-1-oxa-7-azaspiro(4.5)decane; D001372:Aza Compounds; D007651:Keto Acids; D064729:Neurokinin-1 Receptor Antagonists; D013141:Spiro Compounds; D013373:Substance P