Preclinical studies of fluvastatin

Fluvastatin is the first entirely synthetic inhibitor of HMG-CoA reductase that has been extensively investigated. According to the studies presented in this review, fluvastatin is a potent inhibitor of HMG-CoA reductase in vitro, a potent inhibitor of cholesterol biosynthesis in cultured cells and in vivo in rats, and a potent hypocholesterolemic agent in several animal species. Inhibition of liver cholesterol synthesis by fluvastatin leads to increased expression of LDL receptors on the cell surface. This in turn leads to increased turnover in circulating LDL particles, thus decreasing total blood cholesterol. The observation that fluvastatin, beyond its lipid lowering effect, at therapeutic concentrations may affect early events of atherogenesis by inhibiting arterial myocyte migration and proliferation and by interfering with cellular cholesterol disposition, adds antiatherosclerotic properties to this drug. Fluvastatin possesses pharmacokinetic properties desirable for inhibitors of HMG-CoA reductase, and thus of cholesterol biosynthesis. Fluvastatin is almost completely absorbed after oral administration in all species, is largely extracted and biotransformed by the liver, and exhibits a short half-life. Furthermore, a major portion of fluvastatin and its metabolites is preferentially excreted into bile, thus minimizing the systemic burden. The drug and its metabolites are readily excreted and show no retention in body tissues. Safety of fluvastatin after acute and chronic administration was evaluated in various animal species. The results indicate that fluvastatin has different species-specific target organs at doses many times higher than those estimated in man. In conclusion, fluvastatin is a well tolerated and highly effective drug. Thus, it may be considered an important drug in the therapeutic armamentarium available for the treatment of hypercholesterolemia and for the prevention of atherosclerosis.