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The in vivo and in vitro phase I metabolism of FYL‐67, a novel oxazolidinone antibacterial drug, studied by LC‐MS/MS
Author(s) -
Sang Zitai,
Long Haiyue,
Yang Tao,
Ye Weiwei,
Yang Xiaoyan,
Chen Gong,
Wang Zhenling,
Luo Youfu
Publication year - 2016
Publication title -
drug testing and analysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 54
eISSN - 1942-7611
pISSN - 1942-7603
DOI - 10.1002/dta.1887
Subject(s) - in vivo , chemistry , in vitro , metabolism , microsome , metabolic pathway , biotransformation , drug metabolism , metabolite , amide , tandem mass spectrometry , hydroxymethyl , pharmacology , biochemistry , chromatography , mass spectrometry , stereochemistry , enzyme , biology , microbiology and biotechnology
In our previous study, FYL‐67, a novel linezolid analogue with the morpholinyl ring replaced by a 4‐(pyridin‐2‐yl)‐1 H ‐pyrazol‐1‐yl group, was demonstrated to own an excellent activity against Gram‐positive organisms,such as methicillin‐resistant Staphylococcus aureus (MRSA). However, metabolic biotransformation was not investigated. This study was performed to identify the phase I metabolites of FYL‐67 using liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). The chemical structures were confirmed by comparison with corresponding chemical standards obtained internal. Primary elucidation of the metabolic pathway of FYL‐67 in vitro was performed using liver preparations (microsomes and hepatocytes) from rats and humans, and SD (Sprague Dawley, rat, rattus norvegicus ) rats were used for the study of in vivo approach. To the end, two metabolites (M 1 and M 2 ) were detected after in vitro as well as in vivo experiments. Based on LC‐MS/MS analyses, the metabolites were demonstrated to be 5‐(aminomethyl)‐3‐(3‐fluoro‐4‐(4‐(pyridin‐2‐yl)‐1 H ‐pyrazol‐1‐yl)phenyl)oxazolidin‐2‐one (M 1 ) and 3‐(3‐fluoro‐4‐(4‐(pyridin‐2‐yl)‐1 H ‐pyrazol‐1‐yl)phenyl)‐5‐(hydroxymethyl)oxazolidin‐2‐one (M 2 ). Amide hydrolysis at acetyl group of FYL‐67 leading to the formation of M 1 was observed and suggested to play a major role in both in vivo and in vitro phase I metabolism of FYL‐67. M 1 was demonstrated to undergo a further oxidation to form M 2 . In addition, the results indicated no species difference existing between rats and humans. The outcomes of our research can be utilized for the development and validation of the analytical method for the quantification of FYL‐67 as well as its metabolites in biological samples. Furthermore, it is helpful to conduct studies of pharmacodynamics and toxicodynamics. Copyright © 2015 John Wiley & Sons, Ltd.