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Identification
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.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Salts Not Available
Brand names
Name Company
Ezedoc
Ezetib
Ezetrol
Maxetibe
Zemitra
Zetavim
Zetia
Zient
Brand mixtures
Brand Name Ingredients
Inegy Simvastatin + Ezetimibe
Liptruzet Atorvastatin + Ezetimibe
Categories
  • Anticholesteremic Agents
  • Cholesterol Absorption Inhibitors
CAS number 163222-33-1
Weight Average: 409.4252
Monoisotopic: 409.148949953
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
Plain Text
IUPAC Name
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Beta Lactams
  • Phenylpropylamines
Substructures
  • Hydroxy Compounds
  • Benzyl Alcohols and Derivatives
  • Phenols and Derivatives
  • Amino Ketones
  • Benzene and Derivatives
  • Aliphatic and Aryl Amines
  • Beta Lactams
  • Halobenzenes
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Phenylpropylamines
  • Lactams
  • Azetidines
  • Alcohols and Polyols
  • Aryl Halides
  • Phenyl Esters
  • Anilines
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.
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%).
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Msp singapore co llc
Packagers
Dosage forms
Form Route Strength
Tablet Oral 10 mg
Prices
Unit description Cost Unit
Zetia 10 mg tablet 5.15 USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 7030106 2002-07-25 2022-07-25
United States 5846966 1993-09-21 2013-09-21
Canada 2172149 2000-11-28 2014-09-14
Properties
State solid
Experimental Properties
Property Value Source
melting point 163°C FDA label
water solubility Insoluble FDA label
logP 4.5 Not Available
Predicted Properties
Property Value Source
water solubility 8.46e-03 g/l ALOGPS
logP 4.14 ALOGPS
logP 4.56 ChemAxon
logS -4.7 ALOGPS
pKa (strongest acidic) 9.48 ChemAxon
pKa (strongest basic) -3 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 3 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 60.77 ChemAxon
rotatable bond count 6 ChemAxon
refractivity 108.86 ChemAxon
polarizability 41.64 ChemAxon
References
Synthesis Reference Not Available
General Reference
  1. Garcia-Calvo M, Lisnock J, Bull HG, Hawes BE, Burnett DA, Braun MP, Crona JH, Davis HR Jr, Dean DC, Detmers PA, Graziano MP, Hughes M, Macintyre DE, Ogawa A, O’neill KA, Iyer SP, Shevell DE, Smith MM, Tang YS, Makarewicz AM, Ujjainwalla F, Altmann SW, Chapman KT, Thornberry NA: The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8132-7. Epub 2005 May 31. Pubmed
External Links
Resource Link
KEGG Drug D01966 Link_out
PubChem Compound 150311 Link_out
PubChem Substance 46507625 Link_out
ChemSpider 132493 Link_out
ChEBI 49040 Link_out
ChEMBL 49040 Link_out
Therapeutic Targets Database DAP000717 Link_out
PharmGKB PA10816 Link_out
Drug Product Database 2247521 Link_out
RxList http://www.rxlist.com/cgi/generic/ezetimibe.htm Link_out
Drugs.com http://www.drugs.com/ezetimibe.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Ezetimibe Link_out
ATC Codes
  • C10AX09
AHFS Codes
  • 24:06.05
PDB Entries Not Available
FDA label show (321 KB)
MSDS show (281 KB)
Interactions
Drug Interactions
Drug Interaction
Cholestyramine Cholestyramine may decrease the levels of ezetimibe.
Cyclosporine Cyclosporine may increase the therapeutic and adverse effects of ezetimibe.
Warfarin If ezetimibe is added to warfarin, a coumarin anticoagulant, the International Normalized Ratio (INR) should be appropriately monitored.
Food Interactions
  • Take without regard to meals.
Targets

1. Sterol O-acyltransferase 1

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: human
UniProt ID: P35610 Link_out
Gene: SOAT1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Singh A, Basit A, Banerjee UC: Burkholderia cenocepacia: a new biocatalyst for efficient bioreduction of ezetimibe intermediate. J Ind Microbiol Biotechnol. 2009 Nov;36(11):1369-74. Epub 2009 Aug 8. Pubmed
  2. Costet P: Molecular pathways and agents for lowering LDL-cholesterol in addition to statins. Pharmacol Ther. 2010 Mar 19. Pubmed
  3. Wang HH, Portincasa P, Mendez-Sanchez N, Uribe M, Wang DQ: Effect of ezetimibe on the prevention and dissolution of cholesterol gallstones. Gastroenterology. 2008 Jun;134(7):2101-10. Epub 2008 Mar 10. Pubmed

2. Niemann-Pick C1-like protein 1

Pharmacological action: yes
Actions: 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: human
UniProt ID: Q9UHC9 Link_out
Gene: NPC1L1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Altmann SW, Davis HR Jr, Zhu LJ, Yao X, Hoos LM, Tetzloff G, Iyer SP, Maguire M, Golovko A, Zeng M, Wang L, Murgolo N, Graziano MP: Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science. 2004 Feb 20;303(5661):1201-4. Pubmed
  2. Wang J, Williams CM, Hegele RA: Compound heterozygosity for two non-synonymous polymorphisms in NPC1L1 in a non-responder to ezetimibe. Clin Genet. 2005 Feb;67(2):175-7. Pubmed
  3. Sudhop T, Lutjohann D, von Bergmann K: Sterol transporters: targets of natural sterols and new lipid lowering drugs. Pharmacol Ther. 2005 Mar;105(3):333-41. Epub 2004 Dec 9. Pubmed
  4. Garcia-Calvo M, Lisnock J, Bull HG, Hawes BE, Burnett DA, Braun MP, Crona JH, Davis HR Jr, Dean DC, Detmers PA, Graziano MP, Hughes M, Macintyre DE, Ogawa A, O’neill KA, Iyer SP, Shevell DE, Smith MM, Tang YS, Makarewicz AM, Ujjainwalla F, Altmann SW, Chapman KT, Thornberry NA: The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8132-7. Epub 2005 May 31. Pubmed
  5. von Bergmann K, Sudhop T, Lutjohann D: Cholesterol and plant sterol absorption: recent insights. Am J Cardiol. 2005 Jul 4;96(1A):10D-14D. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

3. Aminopeptidase N

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: human
UniProt ID: P15144 Link_out
Gene: ANPEP Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Kramer W, Girbig F, Corsiero D, Pfenninger A, Frick W, Jahne G, Rhein M, Wendler W, Lottspeich F, Hochleitner EO, Orso E, Schmitz G: Aminopeptidase N (CD13) is a molecular target of the cholesterol absorption inhibitor ezetimibe in the enterocyte brush border membrane. J Biol Chem. 2005 Jan 14;280(2):1306-20. Epub 2004 Oct 19. Pubmed
Enzymes

1. UDP-glucuronosyltransferase 1-1

Actions: substrate

UDPGT 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 Link_out
Gene: UGT1A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Oswald S, Nassif A, Modess C, Keiser M, Ulrich A, Runge D, Hanke U, Lutjohann D, Engel A, Weitschies W, Siegmund W: Drug interactions between the immunosuppressant tacrolimus and the cholesterol absorption inhibitor ezetimibe in healthy volunteers. Clin Pharmacol Ther. 2011 Apr;89(4):524-8. Epub 2011 Mar 2. Pubmed
  2. Kosoglou T, Statkevich P, Johnson-Levonas AO, Paolini JF, Bergman AJ, Alton KB: Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clin Pharmacokinet. 2005;44(5):467-94. Pubmed

2. UDP-glucuronosyltransferase 1-3

Actions: substrate

UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds

UniProt ID: P35503 Link_out
Gene: UGT1A3 Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Oswald S, Nassif A, Modess C, Keiser M, Ulrich A, Runge D, Hanke U, Lutjohann D, Engel A, Weitschies W, Siegmund W: Drug interactions between the immunosuppressant tacrolimus and the cholesterol absorption inhibitor ezetimibe in healthy volunteers. Clin Pharmacol Ther. 2011 Apr;89(4):524-8. Epub 2011 Mar 2. Pubmed
  2. Kosoglou T, Statkevich P, Johnson-Levonas AO, Paolini JF, Bergman AJ, Alton KB: Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clin Pharmacokinet. 2005;44(5):467-94. Pubmed

3. UDP-glucuronosyltransferase 2B15

Actions: substrate
UniProt ID: P54855 Link_out

References:
  1. Ghosal A, Hapangama N, Yuan Y, Achanfuo-Yeboah J, Iannucci R, Chowdhury S, Alton K, Patrick JE, Zbaida S: Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of ezetimibe (Zetia). Drug Metab Dispos. 2004 Mar;32(3):314-20. Pubmed
  2. Kosoglou T, Statkevich P, Johnson-Levonas AO, Paolini JF, Bergman AJ, Alton KB: Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clin Pharmacokinet. 2005;44(5):467-94. Pubmed

4. UDP-glucuronosyltransferase 2B7

Actions: substrate

Its 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 Link_out
Gene: UGT2B7 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Ghosal A, Hapangama N, Yuan Y, Achanfuo-Yeboah J, Iannucci R, Chowdhury S, Alton K, Patrick JE, Zbaida S: Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of ezetimibe (Zetia). Drug Metab Dispos. 2004 Mar;32(3):314-20. Pubmed
  2. Kosoglou T, Statkevich P, Johnson-Levonas AO, Paolini JF, Bergman AJ, Alton KB: Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clin Pharmacokinet. 2005;44(5):467-94. Pubmed

5. Cytochrome P450 3A4

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 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Kosoglou T, Statkevich P, Johnson-Levonas AO, Paolini JF, Bergman AJ, Alton KB: Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clin Pharmacokinet. 2005;44(5):467-94. Pubmed
Transporters

1. Multidrug resistance protein 1

Actions: substrate

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Oswald S, Nassif A, Modess C, Keiser M, Ulrich A, Runge D, Hanke U, Lutjohann D, Engel A, Weitschies W, Siegmund W: Drug interactions between the immunosuppressant tacrolimus and the cholesterol absorption inhibitor ezetimibe in healthy volunteers. Clin Pharmacol Ther. 2011 Apr;89(4):524-8. Epub 2011 Mar 2. Pubmed

2. Canalicular multispecific organic anion transporter 1

Actions: substrate

Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter

UniProt ID: Q92887 Link_out
Gene: ABCC2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Oswald S, Nassif A, Modess C, Keiser M, Ulrich A, Runge D, Hanke U, Lutjohann D, Engel A, Weitschies W, Siegmund W: Drug interactions between the immunosuppressant tacrolimus and the cholesterol absorption inhibitor ezetimibe in healthy volunteers. Clin Pharmacol Ther. 2011 Apr;89(4):524-8. Epub 2011 Mar 2. Pubmed
  2. de Waart DR, Vlaming ML, Kunne C, Schinkel AH, Oude Elferink RP: Complex pharmacokinetic behavior of ezetimibe depends on abcc2, abcc3, and abcg2. Drug Metab Dispos. 2009 Aug;37(8):1698-702. doi: 10.1124/dmd.108.026146. Epub 2009 May 14. Pubmed

3. Solute carrier organic anion transporter family member 1B1

Actions: substrate

Mediates 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 Link_out
Gene: SLCO1B1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Oswald S, Nassif A, Modess C, Keiser M, Ulrich A, Runge D, Hanke U, Lutjohann D, Engel A, Weitschies W, Siegmund W: Drug interactions between the immunosuppressant tacrolimus and the cholesterol absorption inhibitor ezetimibe in healthy volunteers. Clin Pharmacol Ther. 2011 Apr;89(4):524-8. Epub 2011 Mar 2. Pubmed

4. ATP-binding cassette sub-family G member 5

Actions: substrate
UniProt ID: Q9H222 Link_out

References:
  1. Couture P, Lamarche B: Ezetimibe and bile acid sequestrants: impact on lipoprotein metabolism and beyond. Curr Opin Lipidol. 2013 Jun;24(3):227-32. doi: 10.1097/MOL.0b013e3283613a55. Pubmed

5. Canalicular multispecific organic anion transporter 2

Actions: substrate

May act as an inducible transporter in the biliary and intestinal excretion of organic anions

UniProt ID: O15438 Link_out
Gene: ABCC3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. de Waart DR, Vlaming ML, Kunne C, Schinkel AH, Oude Elferink RP: Complex pharmacokinetic behavior of ezetimibe depends on abcc2, abcc3, and abcg2. Drug Metab Dispos. 2009 Aug;37(8):1698-702. doi: 10.1124/dmd.108.026146. Epub 2009 May 14. Pubmed

6. ATP-binding cassette sub-family G member 2

Actions: substrate

Xenobiotic 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 Link_out
Gene: ABCG2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. de Waart DR, Vlaming ML, Kunne C, Schinkel AH, Oude Elferink RP: Complex pharmacokinetic behavior of ezetimibe depends on abcc2, abcc3, and abcg2. Drug Metab Dispos. 2009 Aug;37(8):1698-702. doi: 10.1124/dmd.108.026146. Epub 2009 May 14. Pubmed

7. ATP-binding cassette sub-family G member 8

Actions: substrate
UniProt ID: Q9H221 Link_out

References:
  1. Couture P, Lamarche B: Ezetimibe and bile acid sequestrants: impact on lipoprotein metabolism and beyond. Curr Opin Lipidol. 2013 Jun;24(3):227-32. doi: 10.1097/MOL.0b013e3283613a55. Pubmed
Carriers
Searched, but no carriers found.
Comments
Drug created on June 13, 2005 07:24 / Updated on June 15, 2013 23:13