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| Name | Ezetimibe | ||||||||||||||||||||||||||||||||||||||||||
| Accession Number | DB00973 (APRD00619) | ||||||||||||||||||||||||||||||||||||||||||
| Type | small molecule | ||||||||||||||||||||||||||||||||||||||||||
| Groups | approved | ||||||||||||||||||||||||||||||||||||||||||
| Description | Ezetimibe is an anti-hyperlipidemic medication which is used to lower cholesterol levels. Specifically, it appears to bind to a critical mediator of cholesterol absorption, the Niemann-Pick C1-Like 1 (NPC1L1) protein on the gastrointestinal tract epithelial cells as well as in hepatocytes. |
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| Structure |
Download: MOL | SDF | SMILES | InChI Display: 2D Structure | 3D Structure |
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| Synonyms | Not Available | ||||||||||||||||||||||||||||||||||||||||||
| Salts | Not Available | ||||||||||||||||||||||||||||||||||||||||||
| Brand names |
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| CAS number | 163222-33-1 | ||||||||||||||||||||||||||||||||||||||||||
| Weight |
Average: 409.4252 Monoisotopic: 409.148949953 |
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| Chemical Formula | C24H21F2NO3 | ||||||||||||||||||||||||||||||||||||||||||
| InChI Key | InChIKey=OLNTVTPDXPETLC-XPWALMASSA-N | ||||||||||||||||||||||||||||||||||||||||||
| InChI |
InChI=1S/C24H21F2NO3/c25-17-5-1-15(2-6-17)22(29)14-13-21-23(16-3-11-20(28)12-4-16)27(24(21)30)19-9-7-18(26)8-10-19/h1-12,21-23,28-29H,13-14H2/t21-,22+,23-/m1/s1
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| IUPAC Name |
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one
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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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| Mass Spec | Not Available | ||||||||||||||||||||||||||||||||||||||||||
| Taxonomy | |||||||||||||||||||||||||||||||||||||||||||
| Kingdom | Organic | ||||||||||||||||||||||||||||||||||||||||||
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| Substructures |
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| Pharmacology | |||||||||||||||||||||||||||||||||||||||||||
| Indication | For use as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, and Apo B in patients with primary (heterozygous familial and non-familial) hypercholesterolemia. | ||||||||||||||||||||||||||||||||||||||||||
| Pharmacodynamics | Ezetimibe is in a class of lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. Ezetimibe, administered alone is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, and Apo B in patients with primary (heterozygous familial and non-familial) hypercholesterolemia. It is also used in combination therapy with HMG-CoA reductase inhibitors. Ezetimibe has a mechanism of action that differs from those of other classes of cholesterol-reducing compounds (HMG-CoA reductase inhibitors, bile acid sequestrants, fibric acid derivatives, and plant stanols). Ezetimibe does not inhibit cholesterol synthesis in the liver, or increase bile acid excretion but instead localizes and appears to act at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of HMG-CoA reductase inhibitors. | ||||||||||||||||||||||||||||||||||||||||||
| Mechanism of action | Ezetimibe localizes and appears to act at the brush border of the small intestine and inhibits the absorption of cholesterol. This leads to a decrease in the delivery of intestinal cholesterol to the liver. | ||||||||||||||||||||||||||||||||||||||||||
| Absorption | After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). When a single 10 mg dose of ezetimibe is given to a fasted, male, adult subject, the pharmacokinetic parameters are as follows: Cmax = 3.5 - 5.5 ng/mL; Tmax = 4- 12 hours. The pharmacokinetic parameters for ezetimibe-glucuronide are as follows: Cmax = 45 - 71 ng/mL; Tmax = 1-2 hours. Food has not impact on the extent of absorption of ezetimibe. However, Cmax increases by 38% with a high-fat meal. | ||||||||||||||||||||||||||||||||||||||||||
| Volume of distribution | Not Available | ||||||||||||||||||||||||||||||||||||||||||
| Protein binding | >90% bound to human plasma protein | ||||||||||||||||||||||||||||||||||||||||||
| Metabolism |
Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary and renal excretion. In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide.
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| Route of elimination | 78% of the dose is excreted into feces. 11% of the dose is excreted into urine. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose. | ||||||||||||||||||||||||||||||||||||||||||
| Half life | 22 hours (both ezetimibe and ezetimibe-glucuronide). | ||||||||||||||||||||||||||||||||||||||||||
| Clearance | Not Available | ||||||||||||||||||||||||||||||||||||||||||
| Toxicity | The most common adverse reactions in the group of patients treated with ezetimibe that led to treatment discontinuation and occurred at a rate greater than placebo were, arthralgia (0.3%), dizziness (0.2%), and gamma-glutamyltransferase increase (0.2%). | ||||||||||||||||||||||||||||||||||||||||||
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| Pathways | Not Available | ||||||||||||||||||||||||||||||||||||||||||
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| Properties | |||||||||||||||||||||||||||||||||||||||||||
| State | solid | ||||||||||||||||||||||||||||||||||||||||||
| Experimental Properties |
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| Synthesis Reference | Not Available | ||||||||||||||||||||||||||||||||||||||||||
| General Reference |
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| PDB Entries | Not Available | ||||||||||||||||||||||||||||||||||||||||||
| FDA label | show (321 KB) | ||||||||||||||||||||||||||||||||||||||||||
| MSDS | show (281 KB) | ||||||||||||||||||||||||||||||||||||||||||
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| Targets |
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Pharmacological action: yes
Actions: inhibitor Catalyzes the formation of fatty acid-cholesterol esters. Plays a role in lipoprotein assembly and dietary cholesterol absorption. In addition to its acyltransferase activity, it may act as a ligase Organism class: humanUniProt ID: P35610 ![]() Gene: SOAT1 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
2. Niemann-Pick C1-like protein 1 Pharmacological action: yesActions: inhibitor Play a major role in cholesterol homeostasis. Is critical for the uptake of cholesterol across the plasma membrane of the intestinal enterocyte. Is the direct molecular target of ezetimibe, a drug that inhibits cholesterol absorbtion. Lack of activity leads to multiple lipid transport defects. The protein may have a function in the transport of multiple lipids and their homeostasis, and may play a critical role in regulating lipid metabolism Organism class: humanUniProt ID: Q9UHC9 ![]() Gene: NPC1L1 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
Pharmacological action: unknown
Actions: other Broad specificity aminopeptidase. Plays a role in the final digestion of peptides generated from hydrolysis of proteins by gastric and pancreatic proteases. May play a critical role in the pathogenesis of cholesterol gallstone disease. May be involved in the metabolism of regulatory peptides of diverse cell types including small intestinal and tubular epithelial cells, macrophages, granulocytes and synaptic membranes from the CNS. Found to cleave antigen peptides bound to major histocompatibility complex class II molecules of presenting cells and to degrade neurotransmitters at synaptic junctions. Is also implicated as a regulator of IL-8 bioavailability in the endometrium, and therefore may contribute to the regulation of angiogenesis. Is used as a marker for acute myeloid leukemia and plays a role in tumor invasion. In case of human coronavirus 229E (HCoV-229E) infection, serves as receptor for HCoV-229E spike glycoprotein. Mediates as well human cytomegalovirus (HCMV) infection Organism class: humanUniProt ID: P15144 ![]() Gene: ANPEP ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
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| Enzymes |
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1. UDP-glucuronosyltransferase 1-1 Actions: substrateUDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX- alpha to form both the IX-alpha-C8 and IX-alpha-C12 monoconjugates and diconjugate UniProt ID: P22309![]() Gene: UGT1A1 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
2. UDP-glucuronosyltransferase 1-3 Actions: substrateUDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds UniProt ID: P35503![]() Gene: UGT1A3 ![]() Protein Sequence: FASTA SNPs: SNPJam Report ![]() References:
3. UDP-glucuronosyltransferase 2B15 Actions: substrateUniProt ID: P54855 ![]() References:
4. UDP-glucuronosyltransferase 2B7 Actions: substrateIts unique specificity for 3,4-catechol estrogens and estriol suggests it may play an important role in regulating the level and activity of these potent and active estrogen metabolites UniProt ID: P16662![]() Gene: UGT2B7 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
Actions: inhibitor
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide UniProt ID: P08684![]() Gene: CYP3A4 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
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| Transporters |
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1. Multidrug resistance protein 1 Actions: substrateEnergy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells UniProt ID: P08183![]() Gene: ABCB1 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
2. Canalicular multispecific organic anion transporter 1 Actions: substrateMediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter UniProt ID: Q92887![]() Gene: ABCC2 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
3. Solute carrier organic anion transporter family member 1B1 Actions: substrateMediates the Na(+)-independent transport of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostaglandin E2, thromboxane B2, leukotriene C3, leukotriene E4, thyroxine and triiodothyronine. May play an important role in the clearance of bile acids and organic anions from the liver UniProt ID: Q9Y6L6![]() Gene: SLCO1B1 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
4. ATP-binding cassette sub-family G member 5 Actions: substrateUniProt ID: Q9H222 ![]() References:
5. Canalicular multispecific organic anion transporter 2 Actions: substrateMay act as an inducible transporter in the biliary and intestinal excretion of organic anions UniProt ID: O15438![]() Gene: ABCC3 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
6. ATP-binding cassette sub-family G member 2 Actions: substrateXenobiotic transporter that may play an important role in the exclusion of xenobiotics from the brain. May be involved in brain-to-blood efflux. Appears to play a major role in the multidrug resistance phenotype of several cancer cell lines. When overexpressed, the transfected cells become resistant to mitoxantrone, daunorubicin and doxorubicin, display diminished intracellular accumulation of daunorubicin, and manifest an ATP- dependent increase in the efflux of rhodamine 123 UniProt ID: Q9UNQ0![]() Gene: ABCG2 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
7. ATP-binding cassette sub-family G member 8 Actions: substrateUniProt ID: Q9H221 ![]() References:
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Searched, but no carriers found.
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