Ezetimibe.

Abstract

Ezetimibe is the first of a new class of drugs that specifically reduces the intestinal absorption of cholesterol. The drug is absorbed into the intestinal epithelial cell and remains associated in great part with the apical cell membrane where it is believed to interfere with the putative sterol transporter system. This apparently prevents both free cholesterol and plant sterols (phytosterols) from being transported into the cell from the intestinal lumen. The mechanism is very different from the reduction produced by phytosterol esters and phytostanol esters that have been documented previously as interfering with the micellar presentation of sterols to the cell surface. The drug is rapidly absorbed and glucuronidated in the intestinal cell before secretion into the blood. Ezetimibe is avidly taken up by the liver from the portal blood and excreted into the bile, resulting in low peripheral blood concentrations. The glucuronide conjugate is hydrolyzed and absorbed and is equally effective in inhibiting sterol absorption. This enterohepatic recycling is responsible for a half-life in the body of more than 20 h. The principle medical benefit appears to be a reduction in low-density lipoprotein cholesterol (LDLc). There is also a reduction in the cholesterol content of chylomicrons, which may provide some reduction in the atherogenic potential of the plasma lipoprotein pool. Triglycerides fall moderately and a modest rise in high-density lipoprotein cholesterol (HDLc) has been consistently observed in groups of treated patients. The maximum mean reduction of LDL cholesterol is approximately 20-25% in small studies at the maximal dose tested of 40 mg/day and the reduction is usually in the 16-20% range at the dosage of 10 mg/day. Most subsequent studies have been completed with the 10 mg/day dose. The medication is effective as a single daily dose due to its long residence time in the body. Combinations of ezetimibe with all available statins have been completed and demonstrate LDLc reductions of approximately 25% as additive effects to any statin dose alone. There are also small additional increases in HDL (2-3%) and reductions in triglycerides (10-15%). Additive effects to statin therapy have also been documented in patients with homozygous familial hypercholesterolemia. Reduction of plant sterols has been demonstrated in phytosterolemia, offering the first drug treatment for this rare inherited disease.