Carcinogen bioassay and mutagenicity studies with the hypolipidemic agent gemfibrozil

Gemfibrozil, a novel hypolipidemic agent identified chemically as 2,2-dimethyl-5-(2,5-xylyoxy) valeric acid, was evaluated for mutagenic potential in in vitro assays with Salmonella typhimurium. For evaluation of tumorigenic potential, gemfibrozil was administered in the diet (0.30, and 300 mg gemfibrozil/kg) to groups of noninbred CD-1 mice (72/sex) and noninbred CD rats (50/sex) for 78 and 104 weeks, respectively. In the bacterial mutagenesis assays, between 100 and 2,500 microgram gemfibrozil/plate failed to induce a significant increase in revertant bacterial colonies. Neither was a mutagenic response in bacterial assays induced at concentrations up to 300 microgram of five in vivo metabolites of gemifibrozil isolated from rat urine/plate. In mice, gemfibrozil did not significantly increase the frequency or the mean latency period of tumors. In rats, the statistically significant increases in hepatocellular tumors and interstitial cell tumors of the testes were dose related. Adrenal medullary and pancreatic acinar tumors were increased in male rats but were inversely dose related. Under the conditions of this assay, gemfibrozil did not elicit a tumorigenic potential in mice and female rats. In male rats and related to the hepatocellular tumor response, the peroxisome proliferation seen did not occur in humans chronically administered hypolipidemics.