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Metabolism of MRX-I, a Novel Antibacterial Oxazolidinone, in Humans: The Oxidative Ring Opening of 2,3-Dihydropyridin-4-One Catalyzed by Non-P450 Enzymes

文献类型：期刊论文

作者Meng, Jian2; Zhong, Dafang2; Li, Liang2; Yuan, Zhengyu3; Yuan, Hong3; Xie, Cen2; Zhou, Jialan2; Li, Chen2; Gordeev, Mikhail Fedorovich1; Liu, Jinqian1
刊名DRUG METABOLISM AND DISPOSITION
出版日期2015-05
卷号43期号:5页码:646-659
ISSN号0090-9556
DOI10.1124/dmd.114.061747
文献子类Article
英文摘要MRX-I is an analog of linezolid containing a 2,3-dihydropyridin-4-one (DHPO) ring rather than a morpholine ring. Our objectives were to characterize the major metabolic pathways of MRX-I in humans and clarify the mechanism underlying the oxidative ring opening of DHPO. After an oral dose of MRX-I (600 mg), nine metabolites were identified in humans. The principal metabolic pathway proposed involved the DHPO ring opening, generating the main metabolites in the plasma and urine: the hydroxyethyl amino propionic acid metabolite MRX445-1 and the carboxymethyl amino propionic acid metabolite MRX459. An in vitro phenotyping study demonstrated that multiple non-cytochrome P450 enzymes are involved in the formation of MRX445-1 and MRX459, including flavin-containing monooxygenase 5, short-chain dehydrogenase/reductase, aldehyde ketone reductase, and aldehyde dehydrogenase (ALDH). (H2O)-O-18 experiments revealed that two O-18 atoms are incorporated into MRX445-1, one in the carboxyethyl group and the other in the hydroxyl group, and three O-18 atoms are incorporated into MRX459, two in the carboxymethyl group and one in the hydroxyl group. Based on these results, the mechanism proposed for the DHPO ring opening involves the metabolism of MRX-I via FMO5-mediated Baeyer-Villiger oxidation to an enol lactone, hydrolysis to an enol, and enol-aldehyde tautomerism to an aldehyde. The aldehyde is reduced by short-chain dehydrogenase/reductase, aldehyde ketone reductase, ALDH to MRX445-1, or oxidized by ALDH to MRX459. Our study suggests that few clinical adverse drug-drug interactions should be anticipated between MRX-I and cytochrome P450 inhibitors or inducers.
WOS关键词SAFETY
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000352002800001
出版者AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
源URL[http://119.78.100.183/handle/2S10ELR8/276561]  
专题上海药物代谢研究中心
通讯作者Chen, Xiaoyan
作者单位1.MicuRx Pharmaceut Inc, Hayward, CA USA
2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 200031, Peoples R China;
3.MicuRx Pharmaceut Inc, Shanghai, Peoples R China;
推荐引用方式
GB/T 7714		 Meng, Jian,Zhong, Dafang,Li, Liang,et al. Metabolism of MRX-I, a Novel Antibacterial Oxazolidinone, in Humans: The Oxidative Ring Opening of 2,3-Dihydropyridin-4-One Catalyzed by Non-P450 Enzymes[J]. DRUG METABOLISM AND DISPOSITION,2015,43(5):646-659.
APA Meng, Jian.,Zhong, Dafang.,Li, Liang.,Yuan, Zhengyu.,Yuan, Hong.,...&Chen, Xiaoyan.(2015).Metabolism of MRX-I, a Novel Antibacterial Oxazolidinone, in Humans: The Oxidative Ring Opening of 2,3-Dihydropyridin-4-One Catalyzed by Non-P450 Enzymes.DRUG METABOLISM AND DISPOSITION,43(5),646-659.
MLA Meng, Jian,et al."Metabolism of MRX-I, a Novel Antibacterial Oxazolidinone, in Humans: The Oxidative Ring Opening of 2,3-Dihydropyridin-4-One Catalyzed by Non-P450 Enzymes".DRUG METABOLISM AND DISPOSITION 43.5(2015):646-659.

入库方式： OAI收割

来源：上海药物研究所

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