| Drug ID: | D284 |
| Drug Name: | Ezetimibe |
| Synonyms: |
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| Type: | small molecule |
| DrugBank ID: |
DB00973
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| DrugBank Description: |
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].
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| PubChem ID: |
150311
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| CasNo: |
163222-33-1
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| Repositioning for NAFLD: |
Yes
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| SMILES: |
O[C@@H](CC[C@@H]1[C@H](N(C1=O)C1=CC=C(F)C=C1)C1=CC=C(O)C=C1)C1=CC=C(F)C=C1
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| Structure: |
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| InChiKey: |
OLNTVTPDXPETLC-XPWALMASSA-N
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| Molecular Weight: |
409.4252
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| DrugBank Targets: |
Niemann-Pick C1-like protein 1; Sterol O-acyltransferase 1; Aminopeptidase N
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| DrugBank MoA: |
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].
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| DrugBank Pharmacology: |
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].
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| DrugBank Indication: |
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].
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| Targets: |
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| Therapeutic Category: |
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