Abstract
Gemfibrozil, a human pharmaceutical agent, causes hepatomegaly and hepatic peroxisome proliferation in rats, which have been associated with hepatocarcinogenesis. Hamsters are less susceptible than rats to peroxisome proliferation, and no hepatotoxicity has been reported in humans using gemfibrozil. The relationship between hepatic peroxisome proliferation in rodents and human cancer risk is unclear. We investigated the metabolism and excretion of [14C]gemfibrozil in male and female Sprague-Dawley rats and Syrian golden hamsters to better understand species differences in gemfibrozil-induced toxicity. Bile-duct cannulated rats and hamsters excreted 99% and 7 to 20% of a single i.v. gemfibrozil dose in bile, respectively. Cumulative urinary and fecal excretion of gemfibrozil-derived radioactivity after a single oral dose (30 or 2000 mg/kg) were dependent on species and, in rats, on dose. Hamsters excreted 90% of the dose in urine. Rats excreted 55 to 60% of the dose in feces after the low dose and 55 to 70% in urine after the high dose, suggesting possible saturation of biliary excretion. Repeated administration of the low dose to male rats did not alter the routes of excretion compared to a single dose. Major metabolites present in urine and bile were the glucuronide conjugates of gemfibrozil, the 4′-ring hydroxylated metabolite, and the meta-benzoic acid metabolite. The extensive urinary excretion of radioactivity by hamsters and enterohepatic recycling in rats suggests that rats were exposed to a much higher effective dose of gemfibrozil, which may in part explain the previously reported species differences in gemfibrozil-induced toxicity.
Footnotes
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Send reprint requests to: Kelly J. Dix, Ph.D., Research Triangle Institute, 3040 Cornwallis Rd., P.O. Box 12194, Research Triangle Park, NC 27709-2194. E-mail: kjd{at}rti.org
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This work was supported by National Institute of Environmental Health Sciences Contracts N01-ES-15329 and N01-ES-75407.
- Abbreviations used are::
- GEM
- gemfibrozil
- TFA
- trifluoroacetic acid
- HPLC
- high-pressure liquid chromatography
- LSS
- liquid scintillation spectrometry
- Received May 18, 1998.
- Accepted August 31, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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