Background-Ezetimibe has been shown to inhibit cholesterol absorption in animal models, but studies on cholesterol absorption in humans have not been performed thus far. Methods and Results-The effect of ezetimibe (10 mg/d) on cholesterol absorption and synthesis, sterol excretion, and plasma concentrations of cholesterol and noncholesterol sterols was investigated in a randomized, double-blind, placebo-controlled, crossover study in 18 patients with mild to moderate hypercholesterolemia. Treatment periods lasted 2 weeks with an intervening 2-week washout period. Fractional cholesterol absorption rates averaged 49.8Ϯ13.8% on placebo and 22.7Ϯ25.8% on ezetimibe, indicating a reduction of 54% (geometric mean ratio; PϽ0.001). Cholesterol synthesis increased by 89% from 931Ϯ1027 mg/d on placebo to 1763Ϯ1098 mg/d on ezetimibe (PϽ0.001), while the ratio of lathosterol-to-cholesterol, an indirect marker of cholesterol synthesis, was increased by 72% (PϽ0.001). Bile acid synthesis was insignificantly increased (placebo: 264Ϯ209 mg/d, ezetimibe: 308Ϯ184 mg/d; Pϭ0.068). Mean percent changes from baseline for LDL and total cholesterol after ezetimibe treatment were Ϫ20.4% and Ϫ15.1%, respectively (PϽ0.001 for both), whereas campesterol and sitosterol were decreased by Ϫ48% and Ϫ41%, respectively. Conclusion-In humans, ezetimibe inhibits cholesterol absorption and promotes a compensatory increase of cholesterol synthesis, followed by clinically relevant reductions in LDL and total cholesterol concentrations. Ezetimibe also reduces plasma concentrations of the noncholesterol sterols sitosterol and campesterol, suggesting an effect on the absorption of these compounds as well.

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Food supplementation with PSE impairs endothelial function, aggravates ischemic brain injury, effects atherogenesis in mice, and leads to increased tissue sterol concentrations in humans. Therefore, prospective studies are warranted that evaluate not only effects on cholesterol reduction, but also on clinical endpoints.

The disposition and sterol-lowering effects of ezetimibe are modified by metabolic degradation of the drug via intestinal UGT1A1 and either intestinal or hepatic secretion (or both) via P-gp and MRP2.