CHOLESTEROL-LOWERING EFFECT OF AN ACYL-COENZYME-A - CHOLESTEROL ACYLTRANSFERASE INHIBITOR, FR145237, IN HYPERCHOLESTEROLEMIC RABBITS FED A HIGH-CHOLESTEROL DIET AND A CHOLESTEROL-FREE CASEIN DIET

Cholesterol-lowering effects of a new acyl-coenzyme A:cholesterol acyl transferase (ACAT) inhibitor, FR145237, in hypercholesterolemic rabbit s fed a high-cholesterol diet or a cholesterol-free casein diet were e valuated. In the cholesterol-fed rabbits, FR145237 at the doses of 0.0 32, 0.1, and 0.32 mg/kg/day (0.060, 0.19, and 0.60 mu mol/kg/day) redu ced the plasma cholesterol level by 37%, 70%, and 94%, respectively. C holesterol content in the liver was reduced at 0.1 and 0.32 mg/kg/day (0.19 and 0.60 mu mol/kg/day). Cholesterol and phospholipid concentrat ions in the gallbladder bile was also reduced by FR145237 treatment, b ut bile acids concentration was not affected. In the hypercholesterole mic rabbits fed a cholesterol-free casein diet, FR145237 also had a pl asma cholesterol-lowering activity but the effective dose [0.5 mg/kg/d ay (0.93 mu mol/kg/day)] was higher than that in cholesterol-fed rabbi ts. Cholesterol content in the liver of the casein-fed rabbits was red uced in a parallel manner. Cholesterol and phospholipid concentrations in the gallbladder bile were not significantly affected, whereas bile acids concentration was significantly elevated by FR145237 treatment. The results suggest that the cholesterol-lowering activity of ACAT in hibitors may be partly due to their effect on cholesterol metabolism i n the liver, especially at the stages of bile acid synthesis, in addit ion to inhibition of cholesterol absorption in the intestine. (C) 1995 Wiley-Liss, Inc.