Mechanism of Action For Zetia (Ezetimibe)

When Zetia® (ezetimibe) came out on the U.S. market in 2002, it was the only cholesterol-lowering medication of its kind. Ezetimibe works by preventing the absorption of cholesterol from the small intestine and into the bloodstream. Specifically, ezetimibe lowers LDL cholesterol (the "bad" cholesterol) by an average of 10 percent. It does this by blocking a protein in the small intestine referred to as NPC1L1, which is needed for cholesterol absorption to occur in the body. Researchers have also identified this protein in the liver. Scientists studying ezetimibe at Wake Forest University in Winston-Salem, N.C., have discovered that this drug may also lower cholesterol levels by blocking this same protein in the liver.

In order to study how ezetimibe reduces cholesterol, the researchers studied mice that had high levels of the NPC1L1 protein in their liver cells. These mice had a 30- to 60-percent increase in blood cholesterol, while the cholesterol levels in their bile was eighteen times lower than normal. The researchers discovered that blocking NPC1L1 activity by administering ezetimibe caused the blood cholesterol levels to return to normal, while the cholesterol levels in the bile increased. These investigators concluded that the NPC1L1 protein may redirect liver cholesterol away from the bile to the bloodstream and cause blood cholesterol levels to increase. This suggests that some of the cholesterol-lowering activity seen with ezetimibe may come from blocking liver NPC1L1.

Since Zetia greatly increased the amount of cholesterol in the bile of these mice, this may explain the rare, but troublesome, side effect of gallstones seen in some patients taking the drug. More studies would be needed to confirm this hypothesis.

Although this study sheds more light on the complexity of cholesterol metabolism, more studies would be needed to determine if the effect of liver NPC1L1 in humans is the same as in mice. If this proves to be true, this protein may become an important target for the development of future cholesterol-lowering drugs.