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Ezetimibe: a selective inhibitor of cholesterol absorption

A.L Catapano*

Dipartimento di Scienze Farmacologiche, Universita degli Studi di Milano, Milano, Italy

* Correspondence: Professor Alberico L. Catapano, PhD, Dipartimento di Scienze Farmacologiche, Universita degli Studi di Milano, Via G. Balzaretti, 9, Milano, 20133 Italy.

Abstract

Ezetimibe is a novel selective cholesterol absorption inhibitor that effectively blocks intestinal absorption of dietary and biliary cholesterol. Ezetimibe undergoes glucuronidation to a single metabolite and is localized in the intestinal wall, where it prevents cholesterol absorption. Enterohepatic recirculation of ezetimibe and the glucoronide ensures repeated delivery to the site of action and limits peripheral exposure. Ezetimibe does not affect the absorption of fat-soluble vitamins or triglycerides. Results from pre-clinical studies in various animal models have shown the lipid-lowering and anti-atherosclerotic properties of ezetimibe as a single agent, and a synergistic effect when combined with a statin. In cholesterol-fed rhesus monkeys, ezetimibe reduced both plasma cholesterol (ED50 = 0·0005 mg.kg–1.day–1) and low-density lipoprotein cholesterol levels in a dose-dependent manner. In apo F knockout mice, ezetimibe reduced serum cholesterol more than 50% and decreased carotid (97%) and aortic (47–87%) atherosclerosis. Ezetimibe inhibited the rise of plasma cholesterol in cholesterol-fed dogs (ED50 = 0·007 mg.kg–1.day–1). Co-administration of ezetimibe and lovastatin in chow-fed dogs synergistically reduced plasma cholesterol to levels lower than those achieved with either agent alone (). These results suggest that ezetimibe combined with a statin may similarly reduce plasma cholesterol levels in patients with hypercholesterolaemia.

Key Words: Cholesterol absorption inhibitor • ezetimibe • pre-clinical studies • atherosclerosis • hypercholesterolaemia • statins

References

  1. van Heek M, France CF, Compton DS, et al. In vivo metabolism-based discovery of a potent cholesterol absorption inhibitor, SCH58235 in the rat and rhesus monkey through the identification of the active metabolites of SCH48461 J Pharmacol Exp Ther. 1997;283:157–163[Abstract/Free Full Text]
  2. van Heek M, Farley C, Compton DS, et al. Comparison of the activity and disposition of the novel cholesterol absorption inhibitor, SCH58235 and its glucuronide, SCH60663 Br J Pharmacol. 2000;129:1748–1754[CrossRef][Web of Science][Medline]
  3. van Heek M, Farley C, Compton D, Hoos L, Davis H. The novel cholesterol absorption inhibitor, ezetimibe, selectively inhibits the intestinal absorption of free cholesterol in the presence and absence of exocrine pancreatic function (Abstr). Atherosclerosis. 2000;151:155
  4. Guerciolini R. Mode of action of orlistat. Int J Obes Relat Metab Disord. 1997;21(Suppl 3):S12–S23
  5. Toplak H, Marhardt K. Reduction of obesity and improvement in metabolic parameters by inhibition of intestinal lipases: current results with orlistat. Acta Med Austriaca. 1998;25:142–145[Web of Science][Medline]
  6. Heck AM, Yanovski JA, Calis KA. Orlistat, a new lipase inhibitor for the management of obesity. Pharmacotherapy. 2000;20:270–279[CrossRef][Web of Science][Medline]
  7. West RJ, Lloyd JK. The effect of cholestyramine on intestinal absorption. Gut. 1975;16:93–98[Abstract/Free Full Text]
  8. Matsui MS, Rozovski SJ. Drug-nutrient interaction. Clin Ther. 1982;4:423–440[Web of Science][Medline]
  9. Zbaida S, Alton K, Shannon D, et al. In vitro metabolism of SCH 58235, 1-(4-fluorophenyl)-3R-[4-fluorophenyl)-3S-hydroxypropyl]-4S-(4-hydroxyphenyl)-2-azetidinone, by liver and kidney slices (Abstr). Montpellier, France12th International Symposium on Microsomes and Drug Oxidations (ISMDO). July 20–24, 1998.
  10. van Heek M, Compton DS, Davis HR. The cholesterol absorption inhibitor, ezetimibe, decreases diet-induced hypercholesterolemia in monkeys. Eur J Pharmacol. 2001;415:79–84[CrossRef][Web of Science][Medline]
  11. Davis HR, Compton DS, Hoos L, Tetzloff G. The cholesterol inhibitor ezetimibe inhibits the development of atherosclerosis in apo E knockout (–/–) mice fed low fat and western diets (Abstr). Atherosclerosis. 2000;151:133
  12. Davis HR, Watkins RW, Compton DS et al. The cholesterol absorption inhibitor ezetimibe (SCH 58235) and lovastatin synergistically lower plasma cholesterol and inhibit the development of atherosclerosis. Metabolism; in press.
  13. Zilversmit DB. Atherogenic nature of triglycerides, postprandial lipemia, and triglyceride-rich remnant lipoproteins. Clin Chem. 1995;41:153–158[Abstract/Free Full Text]
  14. Cohn JS. Postprandial lipemia: emerging evidence for atherogenicity of remnant lipoproteins. Can J Cardiol. 1998;14(Suppl B):18B–27B
  15. Mamo JC, Proctor SD, Smith D. Retention of chylomicron remnants by arterial tissue; importance of an efficient clearance mechanism from plasma. Atherosclerosis. 1998;141(Suppl 1):S63–S69
  16. Havel RJ. Remnant lipoproteins as therapeutic targets. Curr Opin Lipidol. 2000;11:615–620[CrossRef][Web of Science][Medline]
  17. Davis HR, van Heek M, Watkins RW, et al. The hypocholesterolemic activity of the potent cholesterol absorption inhibitor SCH58235alone and in combination with HMG CoA reductase inhibitors (Abstr). Drugs Affecting Lipid Metabolism (DALM). November 1995. Houston, TX
  18. Knopp RH. Drug treatment of lipid disorders. N Engl J Med. 1999;341:498–511[Free Full Text]
  19. Zhu Y, Statkevich P, Kosoglou T, et al. Effect of ezetimibe (SCH 58235) on the activity of drug metabolizing enzymes in vivo (Abstr). Clin Pharmacol Ther. 2000;67:152

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This Article
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