Reduction of Plasma Cholesterol Levels and Induction of Hepatic LDL Receptor by Cerivastatin Sodium (CAS 143201-11-0, BAY w 6228), a New Inhibitor of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase, in Dogs

The effects of cerivastatin sodium (BAY w 6228), a new type of inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, on plasma cholesterol concentrations and the induction of hepatic LDL receptors were investigated with beagle dogs and Hep G2 cells. Oral administration of cerivastatin (0.01, 0.03, and 0.1 mg/kg per day) for 3 weeks reduced plasma total and very low-density lipoprotein plus low-density lipoprotein (VLDL + LDL) cholesterol concentrations and increased hepatic LDL receptor binding activity in dogs. Scatchard plot analysis revealed a 1.9-fold increase in the maximum binding capacity of hepatic LDL receptors in cerivastatin-treated animals. Similar results were obtained by administration of pravastatin (1.0 and 5.0 mg/kg/day) for 3 weeks. Binding activity of the LDL receptor, as well as receptor mRNA and protein concentrations, were increased in a dose-dependent manner (0.01–1.0 μM) by exposure of Hep G2 cells to cerivastatin. The results suggest that cerivastatin reduces plasma cholesterol concentrations by increasing hepatic LDL receptor expression. The mechanism of lowering cholesterol concentration by cerivastatin was the same as with the other previously examined HMG-CoA reductase inhibitors, but the effects with cerivastatin were apparent at doses much lower than the effective doses of the other drugs. Cerivastatin, therefore, shows potential for clinical use as a potent and efficacious plasma cholesterol-lowering drug.