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Research ArticleArticle

Metabolism of [14C]GSK977779 in Rats and Its Implication with the Observed Covalent Binding

Catherine D. Tsalta, Armina Madatian, Ernest M. Schubert, Fangming Xia, William M. Hardesty, Yanli Deng, Jennifer L. Seymour and Peter D. Gorycki
Drug Metabolism and Disposition September 2011, 39 (9) 1620-1632; DOI: https://doi.org/10.1124/dmd.110.036467
Catherine D. Tsalta
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Armina Madatian
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Ernest M. Schubert
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Fangming Xia
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William M. Hardesty
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Yanli Deng
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Jennifer L. Seymour
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Peter D. Gorycki
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Abstract

GSK977779 is a potent HM74a agonist evaluated for the treatment of dyslipidemia. The disposition and metabolism of [14C]GSK977779 (67.6 μmol/kg p.o.) was studied in male and female rats. The compound was well absorbed and its primary route of elimination was in the feces. Based on metabolite profiling of plasma extracts and urine and bile samples, it was demonstrated that GSK977779 was extensively metabolized in the rat by N-dealkylation, mono- and dioxygenation, reductive and oxidative cleavage of the 1,2,4-oxadiazole ring, and conjugative pathways. After plasma extraction high amounts of nonextractable radioactivity were observed, which were more pronounced in female rats. Size-exclusion chromatography and SDS gel electrophoresis indicated that the majority of the nonextractable radioactivity was covalently bound to plasma proteins. Solubilization of the plasma protein pellet followed by high-performance liquid chromatography and mass spectrometry suggested that a carboxylic acid metabolite derived from oxadiazole ring cleavage may be responsible for the observed covalent binding of the radioactivity to rat plasma proteins.

Footnotes

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

    doi:10.1124/dmd.110.036467.

  • ABBREVIATIONS:

    PAGE
    polyacrylamide gel electrophoresis
    BDC
    bile duct-cannulated
    HPMC
    hydroxypropyl methylcellulose
    LSC
    liquid scintillation counting
    HPLC
    high-performance liquid chromatography
    TCA
    trichloroacetic acid
    MS
    mass spectrometry
    LC-MS/MS
    liquid chromatography/tandem mass spectrometry
    SEC
    size-exclusion chromatography
    MSn
    multiple stage mass spectrometry.

  • Received October 24, 2010.
  • Accepted May 31, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (9)
Drug Metabolism and Disposition
Vol. 39, Issue 9
1 Sep 2011
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Research ArticleArticle

Metabolism of [14C]GSK977779 in Rats and Its Implication with the Observed Covalent Binding

Catherine D. Tsalta, Armina Madatian, Ernest M. Schubert, Fangming Xia, William M. Hardesty, Yanli Deng, Jennifer L. Seymour and Peter D. Gorycki
Drug Metabolism and Disposition September 1, 2011, 39 (9) 1620-1632; DOI: https://doi.org/10.1124/dmd.110.036467

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Research ArticleArticle

Metabolism of [14C]GSK977779 in Rats and Its Implication with the Observed Covalent Binding

Catherine D. Tsalta, Armina Madatian, Ernest M. Schubert, Fangming Xia, William M. Hardesty, Yanli Deng, Jennifer L. Seymour and Peter D. Gorycki
Drug Metabolism and Disposition September 1, 2011, 39 (9) 1620-1632; DOI: https://doi.org/10.1124/dmd.110.036467
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