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 inhibit or of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, on pl asma cholesterol concentrations and the induction of hepatic LDL recep tors were investigated with beagle dogs and Hep G2 cells. Oral adminis tration of cerivastatin (0.01, 0.03, and 0.1 mg/kg per day) for 3 week s reduced plasma total and very low-density lipoprotein pins low-densi ty lipoprotein (VLDL + LDL) cholesterol concentrations and increased h epatic LDL receptor binding activity in dogs. Scatchard plot analysis revealed a 1.9-fold increase in the maximum binding capacity of hepati c 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 mRN A and protein concentrations, were increased in a dose-dependent manne r (0.01-1.0 mu M) by exposure of Hep G2 cells to cerivastatin. The res ults suggest that cerivastatin reduces plasma. cholesterol concentrati ons by increasing hepatic LDL receptor expression. The mechanism of lo wering cholesterol concentration by cerivastatin was the same as with the other previously examined HMG-CoA reductase inhibitors, but the ef fects with cerivastatin were apparent at doses much lower than the eff ective doses of the other drugs. Cerivastatin, therefore, shows potent ial for clinical use as a potent and efficacions plasma cholesterol-lo wering drug.