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The cholesterol absorption inhibitor, ezetimibe, decreases diet-induced hypercholesterolemia in monkeys.
European Journal of Pharmacology 2001 March 10
Ezetimibe (1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone) potently and selectively inhibits the intestinal absorption of cholesterol, thereby reducing plasma cholesterol in preclinical models of hypercholesterolemia. In rhesus monkeys fed a diet containing 375 mg/day of cholesterol, 0.1 mg/kg of ezetimibe completely prevented the doubling of plasma cholesterol normally induced under these dietary conditions (ED(50)=0.0005 mg/kg). Low-density lipoprotein cholesterol (LDL) was dose-dependently reduced, while high-density lipoprotein cholesterol (HDL) and plasma triglyceride were unchanged. A single dose of an ezetimibe analog administered to cynomolgus monkeys fed a single cholesterol-containing meal caused a significant reduction (-69%) of cholesterol in chylomicrons during the postprandial phase without affecting triglyceride content. In rhesus monkeys, apolipoprotein (apo) B(48) concentrations in chylomicrons did not differ between control and the ezetimibe analog, but apo B(100) was significantly reduced in LDL (-41%). These data indicate that these cholesterol absorption inhibitors reduce cholesterol content in chylomicrons, which indirectly leads to a decrease in LDL cholesterol and particle number.
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