Mechanism of Action of Ezetimibe
Ezetimibe reduces blood cholesterol by selectively inhibiting the Niemann-Pick C1-Like 1 (NPC1L1) protein at the brush border of the small intestine, thereby blocking the absorption of dietary and biliary cholesterol without affecting fat-soluble vitamins, triglycerides, or bile acids. 1, 2
Molecular Target and Site of Action
Ezetimibe binds directly to the NPC1L1 sterol transporter, which is the critical protein responsible for cholesterol uptake at the intestinal brush border membrane of enterocytes 1, 2, 3
The drug localizes specifically at the brush border of the small intestine, where it prevents cholesterol from crossing the intestinal wall into enterocytes 4, 2
Ezetimibe undergoes rapid glucuronidation to form ezetimibe-glucuronide, which has even higher affinity for NPC1L1 than the parent compound, and enterohepatic recirculation ensures repeated delivery to the intestinal site of action 3
Mechanism of Cholesterol Reduction
By blocking NPC1L1, ezetimibe inhibits approximately 54% of intestinal cholesterol absorption in hypercholesterolemic patients 1, 3
This blockade decreases the delivery of intestinal cholesterol to the liver, which depletes hepatic cholesterol stores 2
In response to reduced hepatic cholesterol, the liver upregulates LDL receptors on hepatocyte surfaces, which increases clearance of LDL cholesterol from the bloodstream 2
Recent evidence indicates that ezetimibe also promotes brush border membrane-to-lumen cholesterol efflux by 3.5-fold, effectively reversing cholesterol movement and enhancing trans-intestinal cholesterol excretion 5
Cellular Mechanism of NPC1L1 Inhibition
Under normal conditions, cholesterol binding to NPC1L1 triggers clathrin-mediated endocytosis, internalizing both the sterol and the transporter into the enterocyte 6
Ezetimibe prevents NPC1L1 from being incorporated into clathrin-coated vesicles, thereby blocking the sterol-induced internalization process that is essential for cholesterol uptake 6
This mechanism explains why ezetimibe is highly selective: it does not interfere with the absorption of triglycerides, fat-soluble vitamins (A, D, E), or bile acids, which use different transport pathways 1, 4, 2
Clinical Lipid-Lowering Effects
As monotherapy, ezetimibe 10 mg daily reduces LDL-C by approximately 18–20%, along with reductions in total cholesterol, apolipoprotein B, and non-HDL cholesterol 1, 4, 7
When added to ongoing statin therapy, ezetimibe provides an additional 25% reduction in LDL-C beyond the statin effect alone, because the two drugs work through complementary mechanisms—statins inhibit hepatic cholesterol synthesis while ezetimibe blocks intestinal absorption 1, 7
Additional Therapeutic Applications
- Ezetimibe also blocks the absorption of phytosterols (plant sterols such as sitosterol and campesterol), making it FDA-approved for treating homozygous sitosterolemia, a rare genetic disorder of excessive plant sterol absorption 1, 4, 2
Important Caveats
The half-life of both ezetimibe and ezetimibe-glucuronide is approximately 22 hours, and plasma concentration profiles show multiple peaks due to enterohepatic recycling 2
When co-administered with bile acid sequestrants, ezetimibe should be dosed at least 2 hours before or 4 hours after the sequestrant to avoid reduced bioavailability 1, 4
Ezetimibe has minimal drug-drug interaction potential because it does not significantly affect cytochrome P450 enzymes 4, 3