Comparative metabolism and disposition of gemfibrozil in male and female Sprague-Dawley rats and Syrian golden hamsters

Gemfibrozil, a human pharmaceutical agent, causes hepatomegaly and hepatic peroxisome proliferation in rats, which have been associated with hepatocar cinogenesis. Hamsters are less susceptible than rats to peroxisome prolifer ation, and no hepatotoxicity has been reported in humans using gemfibrozil, The relationship between hepatic peroxisome proliferation in rodents and h uman cancer risk is unclear. We investigated the metabolism and excretion o f [C-14]gemfibrozil in male and female Sprague-Dawley rats and Syrian golde n 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 bite, respectively. Cumulative urinary and fecal excretion of gemfibrozil-derived radioactivity after a single or al 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 dos e, suggesting possible saturation of biliary excretion. Repeated administra tion of the law dose to male rats did not alter the routes of excretion com pared to a single dose. Major metabolites present in urine and bile were th e glucuronide conjugates of gemfibrozil, the 4'-ring hydroxylated metabolit e. and the meta-benzoic acid metabolite. The extensive urinary excretion of radioactivity by hamsters and enterohepatic recycling in rats suggests tha t rats were exposed to a much higher effective dose of gemfibrozil, which m ay in part explain the previously reported species differences in gemfibroz il-induced toxicity.