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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
Author(s) -
Matsuo Masahiko,
Aketa Miho,
Ozaki Reiko,
Tomoi Masaaki,
Shimomura Kyoichi
Publication year - 1995
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430360405
Subject(s) - cholesterol , sterol o acyltransferase , medicine , endocrinology , casein , reverse cholesterol transport , chemistry , bile acid , gallbladder , phospholipid , biology , biochemistry , lipoprotein , membrane
Cholesterol‐lowering effects of a new acyl‐coenzyme A:cholesterol acyltransferase (ACAT) inhibitor, FR145237, in hypercholesterolemic rabbits fed a high‐cholesterol die or a cholesterol‐free casein diet were evaluated. In the cholesterol‐fed rabbits, FR145237 at the doses of 0.032, 0.1, and 0.32 mg/kg/day (0.060, 0.19, and 0.60 μmol/kg/day) reduced the plasma cholesterol level by 37%, 70%, and 94%, respectively. Cholesterol content in the liver was reduced at 0.1 and 0.32 mg/kg/day (0.19 and 0.60 μmol/kg/day). Cholesterol and phospholipid concentrations in the gallbladder bile was also reduced by FR145237 treatment, but bile acids concentration was not affected. In the hypercholesterolemic rabbits fed a cholesterol‐free casein diet, FR145237 also had a plasma cholesterol‐lowering activity but the effective dose [0.5 mg/kg/day (0.93 μmol/kg/day)] was higher than that in cholesterol‐fed rabbits. Cholesterol content in the liver of the casein‐fed rabbits was reduced 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 inhibitors may be partly due to their effect on cholesterol metabolism in the liver, especially at the stages of bile acid synthesis, in addition to inhibition of cholesterol absorption in the intestine. © 1995 Wiley‐Liss, Inc.