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Characterization of metabolites of a NK1 receptor antagonist, CJ‐11,972, in human liver microsomes and recombinant human CYP isoforms by liquid chromatography/tandem mass spectrometry
Author(s) -
Prakash Chandra,
Lin Jinyan,
Colizza Kevin,
Miao Zhuang
Publication year - 2007
Publication title -
rapid communications in mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.528
H-Index - 136
eISSN - 1097-0231
pISSN - 0951-4198
DOI - 10.1002/rcm.3153
Subject(s) - chemistry , demethylation , metabolite , microsome , tandem mass spectrometry , moiety , hydroxylation , aldehyde dehydrogenase , liquid chromatography–mass spectrometry , mass spectrometry , aldehyde , stereochemistry , chromatography , biochemistry , enzyme , gene expression , dna methylation , gene , catalysis
The in vitro metabolism of CJ‐11,972, (2‐benzhydryl‐1‐aza‐bicyclo[2.2.2]oct‐3‐yl)‐(5‐ tert ‐butyl‐2‐methoxybenzyl)amine, an NK1 receptor antagonist, was studied in human liver microsomes and recombinant human CYP isoforms. Liquid chromatography/mass spectrometry (LC/MS) and tandem mass spectrometry (LC/MS/MS) coupled to radioactive detection were used to detect and identify the metabolites. CJ‐11,972 was extensively metabolized in human liver microsomes and recombinant human CYP 3A4/3A5 isoforms. A total of fourteen metabolites were identified by a combination of various MS techniques. The major metabolic pathways were due to oxidation of the tert ‐butyl moiety to form an alcohol (M6) and/or O‐demethylation of the anisole moiety. The alcohol metabolite M6 was further oxidized to the corresponding aldehyde (M7) and carboxylic acid (M4). Two unusual metabolites (M13, M17), formed by C‐demethylation of the tert ‐butyl group, were identified as 2‐{3‐[(2‐benzhydryl‐1‐aza‐bicyclo[2.2.2]oct‐3‐ylamino)methyl]‐4‐methoxyphenyl}propan‐2‐ol and (2‐benzhydryl‐1‐aza‐bicyclo[2.2.2]oct‐3‐yl)‐(5‐isopropenyl‐2‐methoxybenzyl)amine. A plausible mechanism for C‐demethylation may involve oxidation of M6 to form an aldehyde metabolite (M7), followed by cytochrome P450‐mediated deformylation leaving an unstable carbon‐centered radical, which would quickly form either the alcohol metabolite M13 and the olefin metabolite M17. Copyright © 2007 John Wiley & Sons, Ltd.