Source of information: Drugbank (External Link). Last updated on: 3rd July 18
*Trade Name used in the content below may not be the same as the HSA-registered product.
Active Ingredient / Synonyms
Ezedoc | Ezetimiba | Ezetimibum | Ezetrol | Ezetimibe |
Ezetimibe is a lipid-lowering compound that inhibits intestinal cholesterol and related phytosterol absorption. The discovery and research of this drug began in the early 1990's, where intravenous administration of radio-labelled compound in rats resulting in subsequent localization of the drug within enterocytes at the intestinal villus, leading to studies of investigating the effect of ezetimibe on intestinal cholesterol absorption [A15202]. Ezetimibe is used as an adjunctive therapy to diet to lower cholesterol levels in primary hyperlipidemia, mixed hyperlipidemia, homozygous familial hypercholesterolemia (HoFH), and homozygous sitosterolemia (phytosterolemia) [FDA Label]. Unlike other classes of cholesterol-reducing compounds including statins and bile acid sequestrants, ezetimibe has a distinct mechanism of action involving the sterol transporter Niemann-Pick C1-Like 1 (NPC1L1), and is the first drug that does not affect absorption of fat-soluble nutrients such as fat-soluble vitamins, triglycerides, or bile acids [A33313]. In genetically NPC1L1-deficient mice, a 70% reduction in intestinal cholesterol absorption was seen and the mice were insensitive to ezetimibe treatment [A15202]. Based on these findings, it is indicated that NPC1L1 plays an essential role in promoting intestinal cholesterol uptake via an ezetimibe-sensitive pathway [A15202]. By interfering with the intestinal uptake of cholesterol and phytosterols, ezetimibe reduces the delivery of intestinal cholesterol to the liver [FDA Label].
Ezetimibe is indicated to reduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with primary hyperlipidemia, alone or in combination with an HMG-CoA reductase inhibitor (statin), reduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia in combination with fenofibrate, reduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH), in combination with atorvastatin or simvastatin, and to reduce elevated sitosterol and campesterol in patients with homozygous sitosterolemia (phytosterolemia) [FDA Label].
Mechanism of Action
Ezetimibe mediates its blood cholesterol-lowering effect via selectively inhibiting the absorption of cholesterol and phytosterol by the small intestine without altering the absorption of fat-soluble vitamins and nutrients [A15202]. The primary target of ezetimibe is the cholesterol transport protein Niemann-Pick C1-Like 1 (NPC1L1) protein. NPC1L1 is expressed at the enterocyte/ gut lumen (apical) as well as the hepatobiliary (canalicular) interface and plays a role in facilitating internalization of free cholesterol into the enterocyte in conjunction with the adaptor protein 2 (AP2) complex and clathrin [A33309]. Once cholesterol in the gut lumen or bile is incorporated into the cell membrane of enterocytes, it can bind to the sterol-sensing domain of NPC1L1 and form a NPC1L1/cholesterol complex. The complex can then be internalized or endocytosed by joining to AP2 clathrin, forming a vesicle complex that is translocated for storage in the endocytic recycling compartment [A33309]. Ezetimibe does not require exocrine pancreatic function for its pharmacological activity; rather, it localizes and appears to act at the brush border of the small intestine. Ezetimibe selectively blocks the NPC1L1 protein in the jejunal brush border, reducing the uptake of intestinal lumen micelles into the enterocyte [A33309]. Overall, ezetimibe causes a decrease in the delivery of intestinal cholesterol to the liver and reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood. While the full mechanism of action of ezetimibe in reducing the entry of cholesterol into both enterocytes and hepatocytes is not fully understood, a study proposed that ezetimibe prevents the NPC1L1/sterol complex from interacting with AP2 in clathrin coated vesicles and induces a conformational change in NPC1L1, rendering it incapable of binding to sterols [A33309]. Another study suggested that ezetimibe disrupts the function of other proteins complexes involved in regulating cholesterol uptake, including the CAV1– annexin 2 heterocomplex [A33309].
Ezetimibe was shown to reduce the levels of total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C), and triglycerides (TG), and increase high-density lipoprotein cholesterol (HDL-C) in patients with hyperlipidemia [FDA Label]. This therapeutic effect was more profound when ezetimibe was co-administered with a statin or fenofibrate compared to either treatment alone [FDA Label]. In clinical trials involving patients with homozygous and heterozygous familial hypercholesterolemia and in those with sitosterolemia, a recommended therapeutic dose of ezetimibe was effective in reducing the LDL levels by 15-20% while increasing HDL-C by 2.5-5% [A33313].
Administration of a single 10-mg dose of ezetimibe in fasted adults resulted in a peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were achieved within 4 to 12 hours (Tmax) [FDA Label]. The Cmax of the major pharmacologically-active metabolite, ezetimibe-glucuronide, was 45 to 71 ng/mL and the Tmax was between 1 and 2 hours [FDA Label]. Food consumption had minimal effect on ezetimibe absorption, but the Cmax was increased by 38% with consumption of high-fat meals [FDA Label]. The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection [FDA Label].
The relative volume of distribution of ezetimibe is 107.5L [F133].
In humans, ezetimibe is rapidly and extensively metabolized via a phase II glucuronide conjugation reaction in the small intestine and liver to form its main phenolic metabolite, ezetimibe glucuronide. The main human liver and/or intestinal uridine 5′-diphosphate (UDP)-glucuronosyltransferase (UGT) enzymes responsible for glucuronidating ezetimibe were shown to be UGT1A1, 1A3 and 2B15 _in vitro_ [A15202]. Minimal phase I reaction involving oxidation of ezetimibe also occurs to form SCH 57871, and human jejunum microsomes also produced trace levels of a benzylic glucuronide (SCH 488128) [A15202]. Ezetimibe glucuronide accounts for 80-90% of the total circulating compound in plasma, and retains some pharmacological activity in inhibiting intestinal cholesterol uptake [FDA Label]. In humans, ezetimibe and ezetimibe-glucuronide constitutes approximately 93% of the total drug in plasma [FDA Label]. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling [FDA Label], and about 20% of the drug distributed is reabsorbed due to enterohepatic re-circulation [F133].
Following oral administration, about 78% and 11% of the administered radio-labelled ezetimibe were recovered in the feces and urine, respectively [FDA Label]. Ezetimibe was the major component in feces and accounted for 69% of the administered dose as unconjugated compound, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose [FDA Label]. High recovery of unchanged parent drug in feces suggests low absorption and/or hydrolysis of ezetimibe-glucuronide secreted in the bile [A15202].
Both ezetimibe and ezetimibe-glucuronide display an approximate half-life of 22 hours [FDA Label].
There is no pharmacokinetic data available on the clearance of ezetimibe.
Oral LD50 and intraperitoneal LD50 in rat were >2000 mg/kg [MSDS]. Estimated oral LD50 values in mouse and dog are >5000 mg/kg and >3000 mg/kg, respectively [MSDS]. One case of accidental overdose occurred in clinical studies in one female patient with homozygous sitosterolemia receiving 120 mg/day for 28 days with no reported clinical or laboratory adverse events [FDA Label]. In case of overdose, symptomatic treatment is recommended [FDA Label].
Although best effort has been made to ensure the information provided is correct and updated, users are advised to visit HSA Official website whenever in doubt. Please see Disclaimers.
We welcome all the content error reporting/feedback. Please contact us @ Text Us!