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Research ArticleArticle

Isolation and identification of novel metabolites of gemfibrozil in rat urine

Brian F. Thomas, Jason P. Burgess, Donna P. Coleman, Nicole M. Scheffler, A. Robert Jeffcoat and Kelly J. Dix
Drug Metabolism and Disposition January 1999, 27 (1) 147-157;
Brian F. Thomas
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Jason P. Burgess
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Donna P. Coleman
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Nicole M. Scheffler
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A. Robert Jeffcoat
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Kelly J. Dix
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Abstract

Gemfibrozil (GEM) is a clofibrate analog used to treat moderate to severe hypertriglyceridemias. In lab animals, GEM causes peroxisome proliferation, an effect that has been associated with hepatocarcinogenesis in rats. In humans, hepatobiliary disorders, but not carcinogenesis, have been associated with GEM therapy. In the present study [14C]GEM was administered orally to rats at a dose of 2000 mg/kg. At various time points, radioactivity in urine was analyzed by liquid scintillation spectrometry, high-pressure liquid chromatography, liquid chromatography/mass spectrometryn, gas chromatography/mass spectroscopy, and nuclear magnetic resonance. Nine metabolites of GEM were identified, some that have not been reported previously. Although the majority of metabolites were glucuronidated, some nonglucuronidated metabolites were identified in urine, including a diol metabolite (both ring methyls hydroxylated), and the product of its further metabolism, the acid-alcohol derivative (ortho ring methyl hydroxylated, meta ring methyl completely oxidized to the acid). Hydroxylation of the aromatic ring also was a common pathway for GEM metabolism, leading to the production of two phenolic metabolites, only one of which was detected in the urine in the nonconjugated or free form. Also of interest was the finding that both acyl and ether glucuronides were produced, including both glucuronide forms of the same metabolite (e.g., 1-O-GlcUA, 5′-COOH-GEM, and 5′-COO-GlcUA-GEM); the positions and functionality of the glucuronide conjugates were identified using base hydrolysis or glucuronidase treatment, in combination with liquid chromatography/MSn and nuclear magnetic resonance.

Footnotes

  • Send reprint requests to: Brian F. Thomas, Ph.D., Research Triangle Institute, 3040 Cornwallis Road, P.O. Box 12194, Research Triangle Park, NC 27709–2194. e-mail: bft{at}rti.org

  • This work was supported by National Institute on Environmental Health Sciences contract numbers NO1-ES-15329 and N01-ES-75407.

  • Abbreviations used are::
    GEM
    GEM
    TFA
    trifluoroacetic acid
    NMR
    nuclear magnetic resonance
    APCI
    atmospheric pressure chemical ionization
    LC/MS
    liquid chromatography/mass spectrometry
    GC/MS
    gas chromatography/MS
    HMBC
    heteronuclear multiple bond correlation
    GlcUA
    glucuronide acid
    • Received May 18, 1998.
    • Accepted September 14, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (1)
Drug Metabolism and Disposition
Vol. 27, Issue 1
1 Jan 1999
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Research ArticleArticle

Isolation and identification of novel metabolites of gemfibrozil in rat urine

Brian F. Thomas, Jason P. Burgess, Donna P. Coleman, Nicole M. Scheffler, A. Robert Jeffcoat and Kelly J. Dix
Drug Metabolism and Disposition January 1, 1999, 27 (1) 147-157;

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Research ArticleArticle

Isolation and identification of novel metabolites of gemfibrozil in rat urine

Brian F. Thomas, Jason P. Burgess, Donna P. Coleman, Nicole M. Scheffler, A. Robert Jeffcoat and Kelly J. Dix
Drug Metabolism and Disposition January 1, 1999, 27 (1) 147-157;
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