Ezetimibe Pharmacodynamics
Ezetimibe selectively inhibits intestinal cholesterol absorption by binding to the Niemann-Pick C1-Like 1 (NPC1L1) protein at the brush border of the small intestine, reducing LDL-C by approximately 18-20% as monotherapy and providing an additional 25% LDL-C reduction when added to statin therapy. 1, 2, 3
Mechanism of Action
Molecular Target and Site of Action
Ezetimibe binds to the NPC1L1 sterol transporter located at the brush border of enterocytes, physically blocking the passage of both dietary and biliary cholesterol across the intestinal wall. 2, 4, 3
The drug localizes specifically at the intestinal brush border membrane, preventing cholesterol uptake into enterocytes without affecting the absorption of fat-soluble vitamins (A, D, E), triglycerides, or bile acids. 1, 2, 3
After oral administration, ezetimibe undergoes rapid and extensive glucuronidation (>80%) in the small intestine and liver to form ezetimibe-glucuronide, which is the pharmacologically active metabolite with even higher affinity for NPC1L1 than the parent compound. 5, 6
Downstream Pharmacodynamic Effects
By blocking intestinal cholesterol absorption, ezetimibe decreases the delivery of cholesterol to the liver, which depletes hepatic cholesterol stores and triggers upregulation of hepatic LDL receptors, thereby increasing clearance of LDL-C from the bloodstream. 3, 5
Ezetimibe inhibits intestinal cholesterol absorption by approximately 54% in hypercholesterolemic patients compared to placebo. 3, 5
The mechanism is fundamentally distinct from statins (which inhibit hepatic cholesterol synthesis) and bile acid sequestrants (which bind bile acids), making ezetimibe complementary to these agents. 2, 4
Clinical Lipid Effects
LDL-Cholesterol Reduction
As monotherapy, ezetimibe 10 mg daily reduces LDL-C by 18-20%. 1, 2, 4
When added to ongoing statin therapy, ezetimibe provides an incremental 25% reduction in LDL-C beyond the statin effect alone. 1, 2
Ezetimibe also reduces total cholesterol, apolipoprotein B, and non-HDL cholesterol. 1, 3
Effects on Other Lipid Parameters
Ezetimibe produces a modest increase in HDL cholesterol (2.5-5%) and a moderate reduction in triglycerides. 2, 7
Unlike bile acid sequestrants, ezetimibe does not adversely affect triglyceride levels. 7
Selectivity Profile
Ezetimibe selectively inhibits cholesterol absorption without affecting fat-soluble vitamin absorption (A, D, E), and clinical trials confirmed no clinically meaningful effect on plasma concentrations of these vitamins. 2, 3
The drug does not impair adrenocortical steroid hormone production. 3
Ezetimibe also blocks absorption of phytosterols (plant sterols), making it useful for treating homozygous sitosterolemia. 1, 2
Pharmacokinetic Properties Relevant to Pharmacodynamics
Absorption and Metabolism
After oral administration of 10 mg, peak plasma concentrations of ezetimibe occur at 4-12 hours, while the active ezetimibe-glucuronide metabolite peaks at 1-2 hours. 3, 6
The drug undergoes extensive enterohepatic recirculation, which ensures repeated delivery to the intestinal site of action and maintains prolonged pharmacodynamic effect. 3, 5, 6
Both ezetimibe and ezetimibe-glucuronide have an elimination half-life of approximately 22 hours, supporting once-daily dosing. 3, 6
Tissue Distribution
Ezetimibe and its glucuronide are highly bound (>90%) to plasma proteins. 3
The drug localizes preferentially at the intestinal wall with limited peripheral exposure, contributing to its favorable safety profile. 5
Clinical Implications
Dosing and Administration
The standard dose is 10 mg orally once daily, which can be taken with or without food. 1, 3
When combined with bile acid sequestrants, ezetimibe should be taken either ≥2 hours before or ≥4 hours after the sequestrant to avoid reduced bioavailability. 1, 6
Cardiovascular Outcomes
The IMPROVE-IT trial demonstrated that adding ezetimibe to moderate-intensity statin therapy in patients with recent acute coronary syndrome reduced major cardiovascular events by approximately 7% over 6 years of follow-up. 1, 4
The SHARP trial showed that simvastatin plus ezetimibe reduced major atherosclerotic cardiovascular disease events compared to placebo over 4.9 years. 1
Safety Profile
Ezetimibe is generally well tolerated with a safety profile comparable to placebo when used as monotherapy. 8, 7
Common adverse effects include upper respiratory tract infection, diarrhea, arthralgia, and sinusitis, which occur at rates similar to placebo. 1, 8
The drug has minimal drug-drug interactions due to lack of significant effects on cytochrome P450 enzymes. 7, 6