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Research ArticleArticle

Identification of Novel Metoclopramide Metabolites in Humans: In Vitro and In Vivo Studies

Upendra A. Argikar, Javier Gomez, Din Ung, Henry P. Parkman and Swati Nagar
Drug Metabolism and Disposition August 2010, 38 (8) 1295-1307; DOI: https://doi.org/10.1124/dmd.110.033357
Upendra A. Argikar
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Javier Gomez
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Din Ung
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Henry P. Parkman
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Swati Nagar
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This article has a correction. Please see:

  • Correction to “Identification of Novel Metoclopramide Metabolites in Humans: In Vitro and In Vivo Studies” - September 01, 2012

Abstract

Metoclopramide (MCP) is frequently used to treat gastroparesis. Previous studies have documented MCP metabolism, but systematic structural identification of metabolites has not been performed. The aim of this study was to better understand MCP metabolism in humans. For examination of in vivo metabolism, a single oral 20-mg MCP dose was administered to eight healthy male volunteers, followed by complete urine collection over 24 h. In vitro incubations were performed in human liver microsomes (HLM) to characterize metabolism via cytochromes P450 and UDP-glucuronosyltransferases and in human liver cytosol for metabolism via sulfotransferases. Urine and subcellular incubations were analyzed for MCP metabolites on a mass spectrometer with accurate mass measurement capability. Five MCP metabolites were detected in vivo, and five additional metabolites were detected in vitro. The five metabolites of MCP identified both in vitro and in vivo were an N-O-glucuronide (M1), an N-sulfate (M2), a des-ethyl metabolite (M3), a hydroxylated metabolite (M4), and an oxidative deaminated metabolite (M5). To our knowledge, metabolites M1 and M4 have not been reported previously. M2 urinary levels varied 22-fold and M3 levels varied 16-fold among eight subjects. In vitro studies in HLM revealed the following additional metabolites: two ether glucuronides (M6 and M8), possibly on the phenyl ring after oxidation, an N-glucuronide (M7), a carbamic acid (M9), and a nitro metabolite (M10). Metabolites M6 to M10 have not been reported previously. In conclusion, this study describes the identification of MCP metabolites in vivo and in vitro in humans.

Footnotes

  • This work was supported in part by a seed grant to support Temple University faculty research collaborations (to H.P.P. and S.N.).

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

    doi:10.1124/dmd.110.033357.

  • ABBREVIATIONS:

    MCP
    metoclopramide
    FDA
    U.S. Food and Drug Administration
    P450
    cytochrome P450
    HLC
    human liver cytosol
    HLM
    human liver microsome(s)
    UDPGA
    UDP-diphosphoglucuronic acid
    HPLC
    high-performance liquid chromatography
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    UGT
    UDP-glucuronosyltransferase
    SULT
    sulfotransferase
    MS
    mass spectrometry
    ESI
    electrospray ionization
    RF
    radiofrequency
    FTMS
    Fourier transformation mass spectrometry
    CID
    collision-induced dissociation
    amu
    atomic mass units
    DIMD
    drug-induced movement disorder.

  • Received March 16, 2010.
  • Accepted April 27, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (8)
Drug Metabolism and Disposition
Vol. 38, Issue 8
1 Aug 2010
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Research ArticleArticle

Identification of Novel Metoclopramide Metabolites in Humans: In Vitro and In Vivo Studies

Upendra A. Argikar, Javier Gomez, Din Ung, Henry P. Parkman and Swati Nagar
Drug Metabolism and Disposition August 1, 2010, 38 (8) 1295-1307; DOI: https://doi.org/10.1124/dmd.110.033357

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Research ArticleArticle

Identification of Novel Metoclopramide Metabolites in Humans: In Vitro and In Vivo Studies

Upendra A. Argikar, Javier Gomez, Din Ung, Henry P. Parkman and Swati Nagar
Drug Metabolism and Disposition August 1, 2010, 38 (8) 1295-1307; DOI: https://doi.org/10.1124/dmd.110.033357
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