Ezetimibe: A Selective Cholesterol Absorption Inhibitor

Edith A. Nutescu, Pharm.D.; Nancy L. Shapiro, Pharm.D.


Pharmacotherapy. 2003;23(11) 

In This Article

Clinical Pharmacology

Ezetimibe acts through selective inhibition of intestinal cholesterol absorption.[8,9,10,11] Experimental studies suggest that ezetimibe prevents dietary and biliary cholesterol uptake and transport across the intestinal wall.[9] Intravenous administration of tritiated ezetimibe to rats with a cannula to the bile duct resulted in localization of radiolabeled drug within enterocytes at the villus tip of the intestinal wall, the site of cholesterol uptake and transepithelial transport (Figure 1).[9,12]

Ezetimibe localizes at the brush border of the small intestine epithelium, preventing cholesterol absorption. (Image courtesy of Harry R. Davis, Ph.D.)

Ezetimibe glucuronide, the primary metabolite, is transported from the liver back to the intestine in bile, and is a more potent inhibitor of cholesterol absorption than ezetimibe itself.[9,13] Hepatic recycling of the glucuronide -- together with its preferential localization in the intestinal lumen -- may explain ezetimibe's high potency and relatively long half-life.[9,13,14]

Ezetimibe selectively inhibits cholesterol absorption, as demonstrated in a 2-week, double-blind, placebo-controlled crossover study of 18 patients with mild hypercholesterolemia and a daily cholesterol intake of 200-500 mg.[15] Ezetimibe reduced the fractional cholesterol absorption by 54% compared with placebo (p<0.001). Plasma LDL and total cholesterol levels, 20.4% and 15.1%, respectively, were significantly (p<0.001) reduced from baseline even though this effect was accompanied by a compensatory increase in cholesterol biosynthesis. Significant reductions in plasma campesterol and sitosterol levels also were observed, which suggests ezetimibe's potential value as treatment for rare lipid metabolism disorders, such as homozygous sitosterolemia.

Ezetimibe differs from orlistat and bile acid sequestrants in that it does not affect pancreatic lipase levels or bile acid sequestration. Ezetimibe did not affect absorption of triglycerides, ethinylestradiol, progesterone, vitamins A and D, taurocholic acid, or fat-soluble vitamins in rodents.[10] Absorption of fat-soluble vitamins also was unaltered in humans after ezetimibe treatment.[16]

The pharmacokinetics of ezetimibe were determined in an open-label study of eight healthy men.[13] After a single administration of radiolabeled ezetimibe 20 mg to the men who had fasted, ezetimibe was rapidly absorbed and extensively metabolized in the small intestine and liver by glucuronidation of the 4-hydroxy-phenyl group. Ezetimibe does not influence the activity of cytochrome P450 (CYP) enzymes. Maximum concentrations of ezetimibe and its glucuronide appeared in the plasma within 2-3 hours. Thereafter, concentrations of ezetimibe and its glucuronide rapidly declined, although both showed numerous peaks suggestive of enterohepatic recirculation.

Ezetimibe has a half-life of approximately 24 hours in humans; in this study, plasma levels of ezetimibe and its glucuronide were detectable for up to 48 hours.[13] Ezetimibe was excreted mostly in the feces (78% of radiolabeled drug), with a minor fraction appearing in the urine (11%). The relatively high level of fecal ezetimibe (69% of the administered dose) suggests limited absorption and possible hydrolysis of the glucuronide metabolite.

The absolute bioavailability of ezetimibe cannot be determined because the compound is virtually insoluble in aqueous media suitable for injection. Concomitant food intake (high-fat or nonfat meals) had no effect on the extent of absorption of ezetimibe. The maximum concen-tration value was increased by 38% when the drug was taken with a high-fat meal. Ezetimibe can be administered with or without food.[17]

Systemic toxicity due to ezetimibe is unlikely to occur since radioactively labeled ezetimibe concentrations are extremely low in the plasma and liver.[9] Minimal adverse effects were reported in clinical trials of ezetimibe alone and in combination with statins, similar to placebo.[17] When used as monotherapy, adverse effects reported in more than 2% of patients in placebo-controlled trials were fatigue, abdominal pain, diarrhea, viral infection, pharyngitis, sinusitis, arthralgia, back pain, and coughing. The frequency of all these effects was similar for ezetimibe and placebo.[17]

Asymptomatic elevation in liver enzymes occurs with all of the existing lipid-lowering agents. The frequency of elevated liver transaminase levels higher than 3 times the upper limit of normal was similar for ezetimibe (0.5%) and placebo (0.3%). When given in combination with statins, transaminase levels increased 1.3% versus 0.4% with ezetimibe alone. These elevated levels were generally asymptomatic, were not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment.[17]

When ezetimibe is given in combination with a statin, liver function tests should be performed at baseline and then monitored according to the recommendations for the particular statin.[17] Myopathy and rhabdomyolysis, reported as a creatine kinase level at least 10 times the upper limit of normal, were rare in patients receiving ezetimibe (0.2% of patients) versus placebo (0.1%), and in those receiving ezetimibe (0.1%) versus ezetimibe combined with statin therapy (0.4%). Therapy discontinuation rates were low in ezetimibe-treated patients and were similar to rates in those who received placebo or statin therapy.[17]

The effective terminal half-life of ezetimibe is 12.8 hours (coefficient of variation 40%) in younger patients and 20.7 hours (coefficient of variation 53%) in elderly patients.[18] Values for maximum plasma concentration and area under the plasma concentration-time curve were slightly higher in elderly patients for both total and ezetimibe glucuronide levels. In contrast, no sex-related pharmacokinetic differences were observed with ezetimibe.[19]

In a multiple-dose study in adolescents (10-18 yrs old) and adults who received ezetimibe 10 mg/day for 7 days, absorption and metabolism of ezetimibe were similar.[20] Based on total ezetimibe concentrations, there were no pharmacokinetic differences between adolescents and adults. Data for pediatric patients younger than 10 years old are not available; therefore, ezetimibe is not recommended for this population.[17]

No adequate well-controlled studies of ezetimibe in pregnant women have been conducted. No evidence of embryolethal effects was found in rats and rabbits given ezetimibe 250, 500, and 1000 mg/kg/day.[17] In rats and rabbits, the frequency of common fetal skeletal findings was increased in those given 1000 mg/kg/day (roughly 10 and 150 times the normal human exposure for rats and rabbits, respectively). Ezetimibe crossed the placenta in rats and rabbits after multiple oral doses. In rat studies, exposure to ezetimibe was found to be up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, caution is advised regarding treatment for nursing mothers.

No dosing adjustments are required for patients with mild hepatic or renal insufficiency, or for geriatric patients.[17] However, coadministration of ezetimibe with a statin is contraindicated in patients with active or severe liver disease and unexplained persistent elevations in serum transaminase levels. Plasma ezetimibe levels are increased 3-4 times and 5-6 times in patients with moderate and severe hepatic insufficiency, respectively. Because unknown effects may occur with increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, ezetimibe is not recommended for these patients.

During in vivo human experiments, no effect of ezetimibe on the activity of CYP isoenzymes 1A2, 2C8/9, 2D6, 3A4, or N-acetyltransferase was observed.[21] It is unlikely that ezetimibe will interact with drugs that are metabolized through this pathway. No pharmacokinetic differences were reported between ezetimibe and digoxin,[22] cimetidine,[23] glipizide,[24] oral contraceptives,[25] or warfarin.[26]

No significant pharmacokinetic effects were seen with ezetimibe in combination with atorvastatin,[27] simvastatin,[28,29] fluvastatin,[30] cerivastatin,[30] lovastatin,[31] or pravastatin.[32] However, further study of these combinations may be warranted, especially in light of emerging data regarding a non-CYP3A4-mediated increase in the active acid forms of statins by agents that inhibit glucuronidation.[33]

In two separate pharmacokinetic studies, concomitant administration of ezetimibe with gemfibrozil[34] and fenofibrate[35] significantly increased the oral bioavailability of total ezetimibe by a factor of 1.7 and 1.5, respectively. However, this increase in relative bioavailability of ezetimibe was not considered clinically significant. Ezetimibe did not significantly affect the bioavailability of gemfibrozil or fenofibrate. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile.[17] Until further clinical data are available, caution is warranted when ezetimibe is coadministered with fibrates.

Concomitant administration of ezetimibe with cholestyramine decreased the mean area under the plasma concentration-time curve for total ezetimibe by approximately 55%.[17] The additive effect of ezetimibe in combination with cholestyramine may be reduced by this interaction. If these agents are administered together, it is recommended that ezetimibe be given either at least 2 hours before or 4 or more hours after administration of a bile acid sequestrant.

The total ezetimibe level increased 12-fold in a patient who underwent renal transplantation and was treated with several drugs, including cyclosporine.[17] Patients who take ezetimibe and cyclosporine should be monitored closely.


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