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SR-12813 lowers plasma cholesterol in beagle dogs by decreasing cholesterol biosynthesis
T A Berkhout1, H M Simon, B Jackson
1Vascular Biology, SmithKline Beecham Pharmaceuticals, Harlow, Herts, UK. Theo_Berkhout_1@sbphrs.com
Abstract:
SR-12813 inhibits cholesterol biosynthesis in Hep G2 cells via an enhanced degradation of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Here we also show that SR-12813 inhibits cholesterol biosynthesis in vivo. A sterol balance study was performed in normolipemic beagle 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 cholesterol absorption were observed. The sterol balance indicated that endogenous 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-cholesterol levels in dogs treated with 25 mg/kg/day SR-12813 were reduced by 56%, confirming a reduction of the cholesterol biosynthesis. Treatment with SR-12813 or the HMG-CoA reductase inhibitor lovastatin resulted 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, cholesterol 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.
Insights
SR-12813 effectively lowers cholesterol by inhibiting its synthesis in vivo. This compound reduces plasma cholesterol and low-density lipoprotein (LDL) cholesterol in dogs, offering a unique mechanism of action.
Area of Science:
- Biochemistry
- Pharmacology
Background:
- Cholesterol biosynthesis is a key target for managing hyperlipidemia.
- 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is the rate-limiting enzyme in cholesterol synthesis.
- Novel inhibitors of cholesterol biosynthesis are sought for therapeutic applications.
Purpose of the Study:
- To investigate the in vivo effects of SR-12813 on cholesterol biosynthesis.
- To determine the impact of SR-12813 on plasma lipid levels and cholesterol metabolism in a preclinical model.
Main Methods:
- Sterol balance study in normolipemic beagle dogs orally administered SR-12813 (10 and 25 mg/kg/day).
- Dual isotope technique to assess intestinal cholesterol absorption.
- Measurement of plasma cholesterol, lathosterol, and cholesterol excretion.
Main Results:
- SR-12813 significantly decreased plasma cholesterol levels in a dose-dependent manner.
- No effect on intestinal cholesterol absorption was observed.
- Endogenous cholesterol synthesis was reduced by up to 37%, confirmed by decreased lathosterol levels.
- Treatment led to a significant reduction in low-density lipoprotein (LDL) cholesterol.
Conclusions:
- SR-12813 inhibits cholesterol biosynthesis in vivo in dogs.
- The compound reduces plasma cholesterol and LDL cholesterol levels.
- SR-12813 exhibits a unique mechanism of action distinct from direct HMG-CoA reductase inhibitors, despite similar in vivo profiles.