title: 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.
abstract: 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). H2 (18)O experiments revealed that two (18)O atoms are incorporated into MRX445-1, one in the carboxyethyl group and the other in the hydroxyl group, and three (18)O 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.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (J.M., D.Z., L.L., C.X., J.Z., C.L., X.C.); MicuRx Pharmaceuticals, Inc., Shanghai, China (Z.Y., H.Y.); and MicuRx Pharmaceuticals, Inc., Hayward, California (M.G., J.L.).
authors.forename: Jian
authors.initials: J
authors.lastname: Meng
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (J.M., D.Z., L.L., C.X., J.Z., C.L., X.C.); MicuRx Pharmaceuticals, Inc., Shanghai, China (Z.Y., H.Y.); and MicuRx Pharmaceuticals, Inc., Hayward, California (M.G., J.L.).
authors.forename: Dafang
authors.initials: D
authors.lastname: Zhong
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (J.M., D.Z., L.L., C.X., J.Z., C.L., X.C.); MicuRx Pharmaceuticals, Inc., Shanghai, China (Z.Y., H.Y.); and MicuRx Pharmaceuticals, Inc., Hayward, California (M.G., J.L.).
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (J.M., D.Z., L.L., C.X., J.Z., C.L., X.C.); MicuRx Pharmaceuticals, Inc., Shanghai, China (Z.Y., H.Y.); and MicuRx Pharmaceuticals, Inc., Hayward, California (M.G., J.L.).
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (J.M., D.Z., L.L., C.X., J.Z., C.L., X.C.); MicuRx Pharmaceuticals, Inc., Shanghai, China (Z.Y., H.Y.); and MicuRx Pharmaceuticals, Inc., Hayward, California (M.G., J.L.).
authors.forename: Hong
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (J.M., D.Z., L.L., C.X., J.Z., C.L., X.C.); MicuRx Pharmaceuticals, Inc., Shanghai, China (Z.Y., H.Y.); and MicuRx Pharmaceuticals, Inc., Hayward, California (M.G., J.L.).
authors.forename: Cen
authors.initials: C
authors.lastname: Xie
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (J.M., D.Z., L.L., C.X., J.Z., C.L., X.C.); MicuRx Pharmaceuticals, Inc., Shanghai, China (Z.Y., H.Y.); and MicuRx Pharmaceuticals, Inc., Hayward, California (M.G., J.L.).
authors.forename: Jialan
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (J.M., D.Z., L.L., C.X., J.Z., C.L., X.C.); MicuRx Pharmaceuticals, Inc., Shanghai, China (Z.Y., H.Y.); and MicuRx Pharmaceuticals, Inc., Hayward, California (M.G., J.L.).
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (J.M., D.Z., L.L., C.X., J.Z., C.L., X.C.); MicuRx Pharmaceuticals, Inc., Shanghai, China (Z.Y., H.Y.); and MicuRx Pharmaceuticals, Inc., Hayward, California (M.G., J.L.).
authors.forename: Mikhail Fedorovich
authors.initials: MF
authors.lastname: Gordeev
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (J.M., D.Z., L.L., C.X., J.Z., C.L., X.C.); MicuRx Pharmaceuticals, Inc., Shanghai, China (Z.Y., H.Y.); and MicuRx Pharmaceuticals, Inc., Hayward, California (M.G., J.L.).
authors.forename: Jinqian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (J.M., D.Z., L.L., C.X., J.Z., C.L., X.C.); MicuRx Pharmaceuticals, Inc., Shanghai, China (Z.Y., H.Y.); and MicuRx Pharmaceuticals, Inc., Hayward, California (M.G., J.L.) xychen@simm.ac.cn.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chen
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism*; D002384:Catalysis; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D006801:Humans; D007189:Indans / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D023303:Oxazolidinones / Q000378:metabolism*; D010084:Oxidation-Reduction; D011728:Pyridones / Q000378:metabolism*; D011758:Pyrroles / Q000378:metabolism*
chemical_list: C546459:2-(3,4-dihydro-2H-pyrrolium-1-yl)-3-oxoindan-1-olate; D000900:Anti-Bacterial Agents; D007189:Indans; D023303:Oxazolidinones; D011728:Pyridones; D011758:Pyrroles; D003577:Cytochrome P-450 Enzyme System; C000590780:contezolid