SR-12813 LOWERS PLASMA-CHOLESTEROL IN BEAGLE DOGS BY DECREASING CHOLESTEROL-BIOSYNTHESIS

SR-12813 inhibits cholesterol biosynthesis in Hep G2 cells via an enha nced degradation of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) re ductase. Here we also show that SR-12813 inhibits cholesterol biosynth esis in vivo. A sterol balance study was performed in normolipemic bea gle dogs. The dogs were given SR-12813 orally at dosages of 10 and 25 mg/kg/day for a period of 9 days. After 7 days plasma cholesterol was decreased by 15% in the 10 mg/kg/day group and by 19% in the 25 mg/kg/ day group. Using a dual isotope technique no effects on intestinal cho lesterol absorption were observed. The sterol balance indicated that e ndogenous synthesis of cholesterol was reduced by 23% in the 10 mg/kg/ day group and by 37% in the 25 mg/kg/day group. Plasma lathosterol-cho lesterol levels in dogs treated with 25 mg/kg/day SR-12813 were reduce d by 56%, cofirming a reduction of the cholesterol biosynthesis. Treat ment with SR-12813 or the HMG-CoA reductase inhibitor lovastatin resul ted in a large decrease in low density lipoprotein (LDL) cholesterol. It is concluded that SR-12813 reduces cholesterol biosynthesis in the dog model which results in a decrease of bile acid excretion, choleste rol excretion and plasma cholesterol level. The in vivo profile of SR- 12813 is very similar to that of direct HMG-CoA reductase inhibitors, although the mode of action of the compound is unique. (C) 1997 Elsevi er Science Ireland Ltd.