Ezetimibe Zetia

Structural Formula Ball-and-Stick Model Space-filling Model

Q = Carbon = Hydrogen ^ = Oxygen = Fluorine ^ = Nitrogen

Year of discovery: 1998; Year of introduction: 2002 (Schering-Plough & Merck); Drug category: Anti-hypolipidemic agent/selective cholesterol absorption inhibitor; Main uses: For the reduction of high cholesterol levels (LDL) as an adjunct to dietary measures, as a monotherapy, or in combination with statins (e.g., atorvastatin, simvastatin); Other brand names: Ezetrol and Ezemibe; Related drugs: Atorvastatin (Lipitor), Lovastatin (Mevacor), Simvastatin (Zocor).

Tight control of the amount of cholesterol in the body is essential for long-term human health. Cholesterol regulation in humans is a complex process in which the level of cholesterol in cell membranes is sensed and coupled to the amount of cholesterol produced by de novo biosynthesis, principally in the liver, but also elsewhere (e.g., brain). The steady state amount of cholesterol is the result of internal biosynthesis, dietary intake, metabolism and clearance (mainly in the form of oxidized sterols as bile acids). The majority of dietary cholesterol is absorbed through the intestines. Since unregulated cholesterol levels, especially elevated LDL, may lead to the development of cardiovascular disease, lowering the absorption of dietary cholesterol is an attractive strategy for therapy with the overabundance of cholesterol typical of the western diet. Such an approach is complementary to the attenuation of cholesterol biosynthesis, e.g., by the use of HMG-CoA reductase inhibitors (see atorvastatin on page 64).

During the late 1990s, a research group at Schering-Plough identified a novel compound, ezetimibe, that selectively inhibits the absorption of cholesterol. In 2002 it was approved and marketed as Zetia. Although several naturally occurring plant sterols (e.g., sterols in soy) can inhibit the absorption of cholesterol, they are much less potent than ezetimibe.1

Ezetimibe acts in the small intestine where it localizes in the brush border (hair-like structures that facilitate the absorption of nutrients). It specifically binds to a protein that normally transports cholesterol through the intestinal wall into the circulation, and in this way reduces the absorption of dietary cholesterol. There is evidence that cholesterol is coupled to a sugar before transport. Ezetimibe apparently interferes either with this process, the transport itself or both. Only a minor fraction of administered ezetimibe is absorbed into the bloodstream, minimizing the amount in the body and lessening the chance of adverse reactions.

Ezetimibe has also been approved as combination therapy with statins (e.g., ezeti-mibe/simvastatin, which is known as Vytorin) since their cholesterol-lowering effects are additive/ When simvastatin (see below) is used alone, the reduction of LDL is about 35%, whereas in combination with ezetimibe it is about 50%.

Simvastatin (Zocorâ„¢)

Ezetimibe is especially beneficial for those who do not tolerate statins because of muscle weakness or pain that can occur with these agents. In rare cases, an extreme toxicity called rhabdomyolysis (a rapid breakdown of muscle fibers and release of toxins into the blood) can result from the use of statins/

1. Exp. Opin. Invest. Drugs 2006, 15, 1337-1351; 2. Nat. Clin. Prac. Card. Med. 2006, 3, 664-672; 3. Exp. Opin. Drug. Safety 2006, 5, 651-666; Refs. p. 83

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