HIGH-DOSE OF FLUVASTATIN SODIUM (XU62-320), A NEW INHIBITOR OF 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE, LOWERS PLASMA-CHOLESTEROL LEVELS IN HOMOZYGOUS WATANABE-HERITABLE HYPERLIPIDEMIC RABBITS

The effects of fluvastatin sodium (XU62-320), a new type of inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on plasma choleste rol and triacylglycerol levels were investigated using homozygous Wata nabe-heritable hyperlipidemic (WHHL) rabbit, an LDL-receptor-deficient animal which expresses a hepatic LDL receptor activity less than 5% t hat of control rabbits. Plasma levels of total, VLDL- and LDL-choleste rol were decreased profoundly after oral administration of fluvastatin at a dose of 50 mg/kg per day for 4 weeks, Plasma triacylglycerol lev els were not affected by fluvastatin. Hepatic HMG-CoA reductase activi ty increased by 3-fold and hepatic LDL receptor activity increased by only 3.7-fold, as calculated by Scatchard plot analysis, with fluvasta tin administration for 4 weeks, and the hepatic mRNA level for the rab bit LDL receptor was increased by 3-fold. Combined administration of f luvastatin (50 mg/kg per day) and cholestyramine, a bile acid sequestr ant resin, at a level of 2% of the diet for 4 weeks more profoundly de creased plasma total, VLDL- and LDL-cholesterol levels with induction of hepatic cholesterol 7 alpha-hydroxylase and no further induction of the hepatic LDL receptor, Plasma triacylglycerol levels were increase d by the combination treatment. These results suggest that high dose o f fluvastatin sodium is effective in lowering plasma cholesterol level s in homozygous WHHL rabbits through the shared mechanisms involving d ecrease in production and secretion of cholesterol from the liver and the induction of hepatic LDL receptor. Additional effect of cholestyra mine on decrease in plasma cholesterol levels seems to be due to the f urther decrease in hepatic cholesterol secretion by up-regulation of h epatic cholesterol 7 alpha-hydroxylase.