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Research ArticleArticle

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

Jian Meng, Dafang Zhong, Liang Li, Zhengyu Yuan, Hong Yuan, Cen Xie, Jialan Zhou, Chen Li, Mikhail Fedorovich Gordeev, Jinqian Liu and Xiaoyan Chen
Drug Metabolism and Disposition May 2015, 43 (5) 646-659; DOI: https://doi.org/10.1124/dmd.114.061747
Jian Meng
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.)
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Dafang Zhong
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.)
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Liang Li
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.)
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Zhengyu Yuan
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.)
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Hong Yuan
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.)
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Cen Xie
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.)
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Jialan Zhou
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.)
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Chen Li
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.)
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Mikhail Fedorovich Gordeev
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.)
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Jinqian Liu
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.)
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Xiaoyan Chen
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.)
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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). 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 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.

Footnotes

    • Received November 7, 2014.
    • Accepted February 18, 2015.
  • dx.doi.org/10.1124/dmd.114.061747.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (5)
Drug Metabolism and Disposition
Vol. 43, Issue 5
1 May 2015
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Research ArticleArticle

Metabolism of Antibacterial Oxazolidinone MRX-I in Humans

Jian Meng, Dafang Zhong, Liang Li, Zhengyu Yuan, Hong Yuan, Cen Xie, Jialan Zhou, Chen Li, Mikhail Fedorovich Gordeev, Jinqian Liu and Xiaoyan Chen
Drug Metabolism and Disposition May 1, 2015, 43 (5) 646-659; DOI: https://doi.org/10.1124/dmd.114.061747

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Research ArticleArticle

Metabolism of Antibacterial Oxazolidinone MRX-I in Humans

Jian Meng, Dafang Zhong, Liang Li, Zhengyu Yuan, Hong Yuan, Cen Xie, Jialan Zhou, Chen Li, Mikhail Fedorovich Gordeev, Jinqian Liu and Xiaoyan Chen
Drug Metabolism and Disposition May 1, 2015, 43 (5) 646-659; DOI: https://doi.org/10.1124/dmd.114.061747
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