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
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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
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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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