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Pharmacology of ezetimibe

M. van Heek and H. Davis1

Schering-Plough Research Institute, Kenilworth, New Jersey, U.S.A.

1 Correspondence: Harry R. Davis, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033-1300, U.S.A.

Abstract

Ezetimibe is the first of the cholesterol absorption inhibitors, a novel class of lipid modifying drugs, which potently inhibit the absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides or bile acids. Ezetimibe localizes in the brush border of the small intestinal enterocytes and reduces the uptake of cholesterol into the enterocytes. This has the net effect of inhibiting cholesterol absorption by keeping the cholesterol in the intestinal lumen, allowing it to be excreted.

Pre-clinical studies demonstrated that ezetimibe was glucuronidated to a single metabolite localized at the intestinal wall, where it prevented cholesterol absorption. It was found that enterohepatic re-circulation of ezetimibe and/or its glucuronide ensured repeated delivery to the site of action and limited peripheral exposure. Ezetimibe had no effect on the activity of major drug metabolizing enzymes (CYP450), which reduces any potential drug-drug interactions with other medications.

Pre-clinical models also demonstrated the lipid-lowering and anti-atherosclerosic properties of ezetimibe as a single agent, and showed its synergistic effect in combination with HMG CoA reductase inhibitors (‘statins‘). In cholesterol-fed rhesus monkeys, ezetimibe reduced both plasma cholesterol (ED50 = 0·0005 mg. kg–1. day–1) and LDL cholesterol in a dose-dependent manner. Plasma cholesterol levels were also reduced in dogs (ED50 = 0·007 mg.kg–1.day–1) and in hamsters (ED50 = 0·04 mg . kg–1 . day–1) fed cholesterol-containing diets. In apo E knockout mice, a model of atherosclerosis, ezetimibe reduced plasma cholesterol levels over 60% primarily through the reduction in VLDL and LDL cholesterol. Ezetimibe inhibited the development of carotid artery (decrease of 97%) and aortic (decrease of 71–87%) atherosclerosis. In non-cholesterol fed dogs, co-administration of ezetimibe with statins resulted in a synergistic reduction in plasma cholesterol levels that was significantly lower than with monotherapy with either agent.

Clinically, ezetimibe (10 mg .day–1) was found to inhibit cholesterol absorption by an average of 54% in hypercholesterolemic individuals (). Plasma total and LDL cholesterol levels were significantly reduced and cholesterol synthesis was increased. These results suggest that in patients with hypercholesterolemia, ezetimibe, in combination with a statin, may produce clinically important additional reductions in plasma cholesterol levels.

Key Words: Cholesterol-lowering drugs • ezetimibe • LDL cholesterol • cholesterol absorption inhibitor • biliary cholesterol

References

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This Article
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