PT  - JOURNAL ARTICLE
AU  - Jian Meng
AU  - Dafang Zhong
AU  - Liang Li
AU  - Zhengyu Yuan
AU  - Hong Yuan
AU  - Cen Xie
AU  - Jialan Zhou
AU  - Chen Li
AU  - MikhaIl Fedorovich Gordeev
AU  - Jinqian Liu
AU  - Xiaoyan Chen
TI  - 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
AID  - 10.1124/dmd.114.061747
DP  - 2015 Feb 20
TA  - Drug Metabolism and Disposition
PG  - dmd.114.061747
4099  - http://dmd.aspetjournals.org/content/early/2015/02/18/dmd.114.061747.short
4100  - http://dmd.aspetjournals.org/content/early/2015/02/18/dmd.114.061747.full
AB  - MRX-I is an analogue 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 to clarify the mechanism underlying the oxidative ring-opening of the DHPO. After an oral dose of MRX-I (600 mg), nine metabolites were identified in humans. The principal metabolic pathway proposed involved 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-P450 enzymes are involved in the formation of MRX445-1 and MRX459, including flavin-containing monooxygenase 5 (FMO5), short-chain dehydrogenase/reductase (SDR), aldehyde ketone reductase (AKR), and aldehyde dehydrogenase (ALDH). H218O experiments revealed that two 18O atoms are incorporated into MRX445-1, one in the carboxyethyl group and the other in the hydroxyl group, and three 18O atoms are incorporated into MRX459, two in the carboxymethyl group and one in the hydroxyl group. Based on these results, the mechanism proposed for 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 SDR, AKR, 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 P450 inhibitors or inducers.