Carcinogenicity and mutagenicity studies with fluvastatin, a new, entirely synthetic HMG-CoA reductase inhibitor.

The HMG-CoA reductase inhibitors are a new and novel class of cholesterol-lowering agents which are widely used worldwide. Fluvastatin is the first entirely synthetic compound in this class and is structurally distinct from fungal metabolite derivatives which are already marketed. As the liver is the site of some toxic effects for these compounds, it was not entirely unexpected that liver cancer was found in rats and/or mice with the first three marketed compounds, lovastatin, pravastatin, and simvastatin. Four lifetime carcinogenicity studies (two rat and two mouse) did not give any evidence that fluvastatin induced liver tumors in rodents. Fluvastatin induced thyroid neoplasms in rats and forestomach papillomas in rodents, as other compounds in this pharmacologic class have also done. The genotoxic potential of fluvastatin has been assessed in vitro using Salmonella typhimurium, Escherichia coli (gene mutations), V79 Chinese hamster cells (HGPRT gene mutations, chromosomal aberrations), rat hepatocyte primary cultures (DNA repair), and BALB/3T3 cells (malignant transformations). Fluvastatin was also tested in vivo for clastogenicity using the mouse bone marrow micronucleus test and by performing a cytogenetic analysis in the rat bone marrow after acute and subacute treatment. In all seven assays fluvastatin was found to be free of any genotoxic potential.