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Identification
NameEzetimibe
Accession NumberDB00973  (APRD00619)
Typesmall molecule
Groupsapproved
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
SynonymsNot Available
SaltsNot Available
Brand names
NameCompany
EzedocNot Available
Ezetib Not Available
EzetrolNot Available
Maxetibe Not Available
Zemitra Not Available
Zetavim Not Available
ZetiaNot Available
Zient Not Available
Brand mixtures
Brand NameIngredients
InegySimvastatin + Ezetimibe
Liptruzet Atorvastatin + Ezetimibe
CategoriesNot Available
CAS number163222-33-1
WeightAverage: 409.4252
Monoisotopic: 409.148949953
Chemical FormulaC24H21F2NO3
InChI KeyInChIKey=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
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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassLactams
SubclassBeta Lactams
Direct parentMonobactams
Alternative parentsPhenylazetidines; Fluorobenzenes; Phenols and Derivatives; Aryl Fluorides; Tertiary Carboxylic Acid Amides; Tertiary Amines; Secondary Alcohols; Enols; Polyamines; Carboxylic Acids; Organofluorides
Substituents2-phenylazetidine; 1-phenylazetidine; fluorobenzene; phenol derivative; aryl fluoride; benzene; aryl halide; tertiary carboxylic acid amide; tertiary amine; secondary alcohol; azetidine; carboxamide group; polyamine; carboxylic acid; carboxylic acid derivative; enol; organohalogen; organofluoride; amine; alcohol; organonitrogen compound
Classification descriptionThis compound belongs to the monobactams. These are compounds comprising beta-lactam ring is alone and not fused to another ring.
Pharmacology
IndicationFor 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.
PharmacodynamicsEzetimibe 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 actionEzetimibe 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.
AbsorptionAfter 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 distributionNot 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 elimination78% 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 life22 hours (both ezetimibe and ezetimibe-glucuronide).
ClearanceNot Available
ToxicityThe 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
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9899
Blood Brain Barrier + 0.9074
Caco-2 permeable - 0.5225
P-glycoprotein substrate Non-substrate 0.6918
P-glycoprotein inhibitor I Non-inhibitor 0.6026
P-glycoprotein inhibitor II Inhibitor 0.5306
Renal organic cation transporter Non-inhibitor 0.8659
CYP450 2C9 substrate Non-substrate 0.8244
CYP450 2D6 substrate Non-substrate 0.7505
CYP450 3A4 substrate Substrate 0.5341
CYP450 1A2 substrate Non-inhibitor 0.7013
CYP450 2C9 substrate Non-inhibitor 0.6125
CYP450 2D6 substrate Non-inhibitor 0.8442
CYP450 2C19 substrate Non-inhibitor 0.5807
CYP450 3A4 substrate Inhibitor 0.796
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.5289
Ames test Non AMES toxic 0.7476
Carcinogenicity Non-carcinogens 0.8328
Biodegradation Not ready biodegradable 0.9853
Rat acute toxicity 2.4979 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9767
hERG inhibition (predictor II) Inhibitor 0.5455
Pharmacoeconomics
Manufacturers
  • Msp singapore co llc
Packagers
Dosage forms
FormRouteStrength
TabletOral10 mg
Prices
Unit descriptionCostUnit
Zetia 10 mg tablet5.15USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States70301062002-07-252022-07-25
United States58469661993-09-212013-09-21
Canada21721492000-11-282014-09-14
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point163°C FDA label
water solubilityInsoluble FDA label
logP4.5Not Available
Predicted Properties
PropertyValueSource
water solubility8.46e-03 g/lALOGPS
logP4.14ALOGPS
logP4.56ChemAxon
logS-4.7ALOGPS
pKa (strongest acidic)9.48ChemAxon
pKa (strongest basic)-3ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count3ChemAxon
hydrogen donor count2ChemAxon
polar surface area60.77ChemAxon
rotatable bond count6ChemAxon
refractivity108.86ChemAxon
polarizability41.64ChemAxon
number of rings4ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Venkataraman Sundaram, Srinivasam Rajan, Vaddadi Ramayya, Sunkara Vardhan, Bulusu Subrahmanyam, Cheemalapati Sasikala, “Polymorphs of ezetimibe and process for preparation thereof.” U.S. Patent US20050171080, issued August 04, 2005.

US20050171080
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
ResourceLink
KEGG DrugD01966
PubChem Compound150311
PubChem Substance46507625
ChemSpider132493
ChEBI49040
ChEMBLCHEMBL1138
Therapeutic Targets DatabaseDAP000717
PharmGKBPA10816
Drug Product Database2247521
RxListhttp://www.rxlist.com/cgi/generic/ezetimibe.htm
Drugs.comhttp://www.drugs.com/ezetimibe.html
WikipediaEzetimibe
ATC CodesC10AX09
AHFS Codes
  • 24:06.05
PDB EntriesNot Available
FDA labelshow(321 KB)
MSDSshow(281 KB)
Interactions
Drug Interactions
Drug
CholestyramineCholestyramine may decrease the levels of ezetimibe.
CyclosporineCyclosporine may increase the therapeutic and adverse effects of ezetimibe.
WarfarinIf ezetimibe is added to warfarin, a coumarin anticoagulant, the International Normalized Ratio (INR) should be appropriately monitored.
Food Interactions
  • Take without regard to meals.

1. Sterol O-acyltransferase 1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Sterol O-acyltransferase 1 P35610 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Niemann-Pick C1-like protein 1 Q9UHC9 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: other

Components

Name UniProt ID Details
Aminopeptidase N P15144 Details

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

1. UDP-glucuronosyltransferase 1-1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-1 P22309 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-3 P35503 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 2B15 P54855 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 2B7 P16662 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

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

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Canalicular multispecific organic anion transporter 1 Q92887 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier organic anion transporter family member 1B1 Q9Y6L6 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
ATP-binding cassette sub-family G member 5 Q9H222 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Canalicular multispecific organic anion transporter 2 O15438 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
ATP-binding cassette sub-family G member 2 Q9UNQ0 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
ATP-binding cassette sub-family G member 8 Q9H221 Details

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

Comments
Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12