title: The in vivo and in vitro phase I metabolism of FYL-67, a novel oxazolidinone antibacterial drug, studied by LC-MS/MS.
abstract: In our previous study, FYL-67, a novel linezolid analogue with the morpholinyl ring replaced by a 4-(pyridin-2-yl)-1H-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 (M1 and M2 ) 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)-1H-pyrazol-1-yl)phenyl)oxazolidin-2-one (M1 ) and 3-(3-fluoro-4-(4-(pyridin-2-yl)-1H-pyrazol-1-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one (M2 ). Amide hydrolysis at acetyl group of FYL-67 leading to the formation of M1 was observed and suggested to play a major role in both in vivo and in vitro phase I metabolism of FYL-67. M1 was demonstrated to undergo a further oxidation to form M2 . 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.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital Sichuan University, and Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, 610041, P. R. China.
authors.forename: Zitai
authors.initials: Z
authors.lastname: Sang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital Sichuan University, and Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, 610041, P. R. China.
authors.forename: Haiyue
authors.initials: H
authors.lastname: Long
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital Sichuan University, and Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, 610041, P. R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital Sichuan University, and Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, 610041, P. R. China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Ye
authors.affiliation: Department of Pharmaceutical and Bioengineering, School of Chemical Engineering, Sichuan University, Chengdu, Sichuan, 610065, P. R. China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital Sichuan University, and Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, 610041, P. R. China.
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital Sichuan University, and Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, 610041, P. R. China.
authors.forename: Zhenling
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital Sichuan University, and Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, 610041, P. R. China.
authors.forename: Youfu
authors.initials: Y
authors.lastname: Luo
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D023303:Oxazolidinones / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D000900:Anti-Bacterial Agents; D023303:Oxazolidinones
keywords: FYL-67; LC-MS/MS; antibacterial; metabolism; oxazolidinone