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.
Hop
Cornelis E C A
CE
Department of Drug Metabolism, Merck Research Laboratories, Rahway, New Jersey, USA. hopce@groton.pfizer.com
Wang
Yanfeng
Y
Kumar
Sanjeev
S
Elipe
Maria Victoria Silva
MV
Raab
Conrad E
CE
Dean
Dennis C
DC
Poon
Grace K
GK
Keohane
Carol-Ann
CA
Strauss
John
J
Chiu
Shuet-Hing L
SH
Curtis
Neil
N
Elliott
Jason
J
Gerhard
Ute
U
Locker
Karen
K
Morrison
Denise
D
Mortishire-Smith
Russell
R
Thomas
Steven
S
Watt
Alan P
AP
Evans
David C
DC
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