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Research ArticleArticle

Metabolism and Pharmacokinetics of Morinidazole in Humans: Identification of Diastereoisomeric Morpholine N+-Glucuronides Catalyzed by UDP Glucuronosyltransferase 1A9

Ruina Gao, Liang Li, Cen Xie, Xingxing Diao, Dafang Zhong and Xiaoyan Chen
Drug Metabolism and Disposition March 2012, 40 (3) 556-567; DOI: https://doi.org/10.1124/dmd.111.042689
Ruina Gao
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Liang Li
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Cen Xie
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Xingxing Diao
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Dafang Zhong
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Xiaoyan Chen
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Abstract

Morinidazole [R,S-1-(2-methyl-5-nitro-1H-imidazol-1-yl)-3-morpholinopropan-2-ol] is a new 5-nitroimidazole class antimicrobial agent. The present study aimed to determine the metabolism and pharmacokinetics of morinidazole in humans and to identify the enzymes responsible for the formation of the major metabolites. Plasma and urine samples were collected before and after an intravenous drip infusion of 500 mg of racemic morinidazole. Ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry revealed 10 metabolites. Morinidazole glucuronidation, followed by renal excretion, was the major elimination pathway, accounting for 35% of the dose. The metabolic pathway displayed regioselectivities and stereoselectivities. Unexpectedly, the nitrogen atom of the morpholine ring, rather than the aliphatic hydroxyl group at the side chain, was glucuronidated to form S-morinidazole glucuronide (M8-1) and R-enantiomer glucuronide (M8-2). The plasma exposure of M8-2 was 6-fold higher than that of M8-1, accounting for 22.9 and 3.96% of the parent drug exposure, respectively. Investigation of morinidazole glucuronidation using human liver microsomes (HLMs) and 12 recombinant UDP glucuronosyltransferases (UGTs) indicated that this biotransformation was mainly catalyzed by UGT1A9. A kinetic study showed that N+-glucuronidation of racemic morinidazole in both HLMs and in UGT1A9 obeyed a typical Michaelis-Menten plot. The Km values for M8-1 and M8-2 formation by HLMs were similar (11.3 and 15.1 mM), but the Vmax values were significantly different (111 and 1660 pmol · min−1 · mg protein−1). Overall, after an intravenous administration, morinidazole and its metabolites were eliminated in humans primarily via renal excretion. The major metabolites were two diastereoisomeric N+-glucuronides, and UGT1A9 played an important role in N+-glucuronidation.

Footnotes

  • This work was supported in part by the National Natural Science Foundation of China [Grant 81173117].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.111.042689.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    N+-glucuronide
    quaternary ammonium-linked glucuronide
    UPLC
    ultraperformance liquid chromatography
    Q-TOF MS
    quadrupole time-of-flight mass spectrometer
    MDF
    mass defect filter
    UGT
    UDP glucuronosyltransferase
    UDPGA
    uridine 5′-diphosphoglucuronic acid
    DMSO
    dimethyl sulfoxide
    HLMs
    human liver microsomes
    NOESY
    nuclear Overhauser enhancement spectroscopy
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    AUC
    area under the plasma concentration-time curve
    CE
    collision energy.

  • Received September 6, 2011.
  • Accepted December 19, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (3)
Drug Metabolism and Disposition
Vol. 40, Issue 3
1 Mar 2012
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Research ArticleArticle

METABOLISM AND PHARMACOKINETICS OF MORINIDAZOLE IN HUMANS

Ruina Gao, Liang Li, Cen Xie, Xingxing Diao, Dafang Zhong and Xiaoyan Chen
Drug Metabolism and Disposition March 1, 2012, 40 (3) 556-567; DOI: https://doi.org/10.1124/dmd.111.042689

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Research ArticleArticle

METABOLISM AND PHARMACOKINETICS OF MORINIDAZOLE IN HUMANS

Ruina Gao, Liang Li, Cen Xie, Xingxing Diao, Dafang Zhong and Xiaoyan Chen
Drug Metabolism and Disposition March 1, 2012, 40 (3) 556-567; DOI: https://doi.org/10.1124/dmd.111.042689
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