Abstract
Novel acyl-coenzyme A:cholesterol acyltransferase inhibitor pactimibe has been evaluated in vivo; it exhibited significant serum cholesterol lowering activities in hamsters and monkeys without affecting non-high density lipoprotein cholesterol levels. The mechanism of the hypocholesterolemic action of pactimibe was examined in normocholesterolemic hamsters in this study. Results with the dual-isotope plasma ratio method indicated that pactimibe inhibits cholesterol absorption from the intestine, reduces cholesteryl ester formation in the liver, and enhances its elimination from the body. The Triton WR-1339 experiment showed that pactimibe inhibited secretion of very low density lipoprotein cholesterol from the liver. These results suggest that pactimibe is likely to have multiple mechanisms of action responsible for its effectiveness in reducing serum cholesterol.
MeSH terms
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Animals
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Anticholesteremic Agents / pharmacology*
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Anticholesteremic Agents / therapeutic use
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Bile / metabolism
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Cholesterol / administration & dosage
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Cholesterol / blood
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Cholesterol / metabolism*
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Cholesterol, VLDL / metabolism
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Cricetinae
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Diabetes Mellitus, Experimental / blood
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Dose-Response Relationship, Drug
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Feces / chemistry
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Hypercholesterolemia / blood
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Hypercholesterolemia / drug therapy
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Indoleacetic Acids / pharmacology*
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Indoleacetic Acids / therapeutic use
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Intestinal Absorption / drug effects
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Liver / drug effects*
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Liver / metabolism
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Macaca fascicularis
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Male
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Mesocricetus
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Phospholipids / blood
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Postprandial Period
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Rats
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Rats, Sprague-Dawley
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Sterol Esterase / metabolism
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Sterol O-Acyltransferase / antagonists & inhibitors*
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Sterol O-Acyltransferase / metabolism
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Time Factors
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Triglycerides / blood
Substances
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Anticholesteremic Agents
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Cholesterol, VLDL
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Indoleacetic Acids
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Phospholipids
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Triglycerides
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Cholesterol
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pactimibe
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Sterol O-Acyltransferase
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Sterol Esterase