LIFIBROL INCREASES HEPATIC CHOLESTEROL 7-ALPHA-HYDROXYLASE ACTIVITY IN SPRAGUE-DAWLEY RATS

The hypocholesterolemic drug lifibrol was administered orally to Sprague-Dawley rats to determine its effects on lipoprotein cholesterol distribution and hepatic HMG-CoA reductase and cholesterol 7 alpha-hydroxylase activities. The effects of lifibrol on those endpoints were compared with the effects of gemfibrozil and lovastatin. When administered to either chow-fed or cholesterol-fed rats, lifibrol (25 or 50 mg/kg/day) caused a redistribution of lipoprotein cholesterol such that HDL increased and VLDL + LDL decreased significantly. Gemfibrozil (30 or 50 mg/kg/day) caused similar changes in lipoprotein cholesterol distribution. in contrast, lovastatin (10 mg/kg/day) decreased both HDL and VLDL + LDL in chow-fed animals, but had no effect in cholesterol-fed animals. Hepatic HMC-CoA reductase activity was increased in rats treated with lifibrol (50 mg/kg/day), gemfibrozil (50 mg/kg/day), and lovastatin (10 mg/kg/day). The most significant finding is that lifibrol was the only drug that increased hepatic cholesterol 7 alpha-hydroxylase activity. This observation in rats separates the mechanism of action of lifibrol from those of the HMG-CoA reductase inhibitors and the fibrates, and suggests that one mechanism of action of lifibrol is to enhance cholesterol elimination through conversion to bile acids. (C) 1994 Wiley-Liss, Inc.