Identification of metabolites of a substance P (neurokinin 1 receptor) antagonist in rat hepatocytes and rat plasma.
Drug Metab Dispos
; 30(8): 937-43, 2002 Aug.
Article
in En
| MEDLINE
| ID: mdl-12124313
ABSTRACT
[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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Spiro Compounds
/
Aza Compounds
/
Substance P
/
Hepatocytes
/
Neurokinin-1 Receptor Antagonists
Type of study:
Diagnostic_studies
Limits:
Animals
Language:
En
Journal:
Drug Metab Dispos
Journal subject:
FARMACOLOGIA
Year:
2002
Document type:
Article
Affiliation country:
United States