Effects of MER-29, a cholesterol synthesis inhibitor, on mammalian tissue lipides

Abstract

MER-29 is a specific inhibitor of cholesterol biosynthesis, and its site of action is located after formation of the steroid nucleus. MER-29 reduced plasma cholesterol of rats within 6 days to levels close to those maintained on chronic administration. Plasma phospholipide was also reduced, but less than cholesterol. A linear relationship exists between the logarithm of the dose and the reduction of plasma cholesterol and phospholipide in the rat. Chronic administration significantly reduced the cholesterol levels of the following tissues in the rat: plasma, erythrocytes, liver, skeletal muscle, lung, adrenal, and aorta. Cholesterol of brain and adipose tissue was not reduced. Liver total lipide was unchanged, and liver and plasma unsaponifiable matter were reduced. In monkeys, oral administration of MER-29 over a 6-month period produced: (a) a reduction of plasma total and α- and β-lipoprotein cholesterol; (b) no effect on plasma phospholipide or α- and β-lipoproteins stainable with Oil Red O; (c) a lowering of erythrocyte cholesterol; (d) a reduction of plasma unsaponifiable matter; this was reduced less than plasma cholesterol because of accumulation of other nonsaponifiable material, which, in one monkey, amounted to 40% of the drop in cholesterol.