SR-12813 lowers plasma cholesterol in beagle dogs by decreasing cholesterol biosynthesis

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 w...

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Bibliographic Details
Published in:Atherosclerosis 1997-09, Vol.133 (2), p.203-212
Main Authors: Berkhout, Theo A, Simon, Helen M, Jackson, Brian, Yates, John, Pearce, Nigel, Groot, Pieter H.E, Bentzen, Craig, Niesor, Eric, Kerns, William D, Suckling, Keith E
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Anticholesteremic Agents - administration & dosage
Anticholesteremic Agents - pharmacology
Biological and medical sciences
Cholesterol - biosynthesis
Cholesterol - blood
Cholesterol synthesis
Cholesterol, Dietary - metabolism
Cholesterol, LDL - blood
Diphosphonates - administration & dosage
Diphosphonates - pharmacology
Dogs
Enzyme Inhibitors - pharmacology
Evaluation Studies as Topic
General and cellular metabolism. Vitamins
High density lipoprotein
Lathosterol
Lipoproteins - blood
Lipoproteins - drug effects
Lovastatin
Lovastatin - pharmacology
Low density lipoprotein
Male
Medical sciences
Pharmacology. Drug treatments
Sitosterol
Sterol balance
Sterols - blood
Sterols - pharmacokinetics
Very low density lipoprotein
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Summary: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.
ISSN:0021-9150
1879-1484
DOI:10.1016/S0021-9150(97)00131-7