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Record Information
Version4.0
StatusExpected but not Quantified
Creation Date2012-09-06 15:16:51 UTC
Update Date2020-02-26 21:40:59 UTC
HMDB IDHMDB0015108
Secondary Accession Numbers
  • HMDB15108
Metabolite Identification
Common NameEzetimibe
DescriptionEzetimibe, also known as zetia or ezedoc, belongs to the class of organic compounds known as monobactams. Monobactams are compounds comprising beta-lactam ring is alone and not fused to another ring. This therapeutic effect was more profound when ezetimibe was co-administered with a statin or fenofibrate compared to either treatment alone . 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 . 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 . Ezetimibe is an extremely weak basic (essentially neutral) compound (based on its pKa). Ezetimibe is a lipid-lowering compound that inhibits intestinal cholesterol and related phytosterol absorption. Oral LD50 and intraperitoneal LD50 in rat were >2000 mg/kg .
Structure
Data?1582753259
Synonyms
ValueSource
EzedocChEBI
EzetimibaChEBI
EzetimibumChEBI
EzetrolChEBI
ZetiaChEBI
(1-(4-Fluorophenyl)-(3R)-(3-(4-fluorophenyl)-(3S)-hydroxypropyl)-(4S)-(4-hydroxyphenyl)-2-azetidinone)HMDB
EzetimibHMDB
Chemical FormulaC24H21F2NO3
Average Molecular Weight409.4252
Monoisotopic Molecular Weight409.148949953
IUPAC Name(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one
Traditional Nameezetimibe
CAS Registry Number163222-33-1
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
InChI Identifier
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
InChI KeyOLNTVTPDXPETLC-XPWALMASSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as monobactams. Monobactams are compounds comprising beta-lactam ring is alone and not fused to another ring.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassLactams
Sub ClassBeta lactams
Direct ParentMonobactams
Alternative Parents
Substituents
  • Monobactam
  • 1-phenylazetidine
  • 2-phenylazetidine
  • 1-hydroxy-2-unsubstituted benzenoid
  • Fluorobenzene
  • Halobenzene
  • Phenol
  • Aryl fluoride
  • Aryl halide
  • Monocyclic benzene moiety
  • Benzenoid
  • Tertiary carboxylic acid amide
  • Azetidine
  • Carboxamide group
  • Secondary alcohol
  • Azacycle
  • Carboxylic acid derivative
  • Organonitrogen compound
  • Organofluoride
  • Organohalogen compound
  • Hydrocarbon derivative
  • Organic oxide
  • Carbonyl group
  • Organopnictogen compound
  • Alcohol
  • Organic oxygen compound
  • Organooxygen compound
  • Aromatic alcohol
  • Organic nitrogen compound
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Ontology
Disposition

Biological location:

Role

Industrial application:

Physical Properties
StateSolid
Experimental Properties
PropertyValueReference
Melting PointNot AvailableNot Available
Boiling PointNot AvailableNot Available
Water Solubility0.0085 g/LNot Available
LogP4.5Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0085 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 Area60.77 ŲChemAxon
Rotatable Bond Count6ChemAxon
Refractivity108.86 m³·mol⁻¹ChemAxon
Polarizability41.64 ųChemAxon
Number of Rings4ChemAxon
BioavailabilityYesChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectrum TypeDescriptionSplash KeyView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-05c6-2945000000-8a37190570bab21d1d02Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positivesplash10-0002-1903310000-633b71d71a358012cf6aSpectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , Positivesplash10-0a6r-0692700000-11f020dfbb889ac85e4eSpectrum
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-000i-1910000000-5b24d4adc8cd3de959fcSpectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-01ox-0149600000-6c8e6056b5e23340ee0eSpectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-02i6-1794200000-9502e8a01ff6f30b9fc1Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-072a-2950000000-eed640a1fd606e7a63b4Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0a4i-0122900000-b96ba99bfc7c99941d6bSpectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0006-1921100000-e17ecfb5ab2d745ce445Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-01pa-4941000000-a0f53760eaaecdb35c3dSpectrum
Biological Properties
Cellular Locations
  • Cytoplasm
  • Membrane
Biospecimen Locations
  • Blood
  • Urine
Tissue LocationsNot Available
Pathways
Normal Concentrations
BiospecimenStatusValueAgeSexConditionReferenceDetails
BloodExpected but not QuantifiedNot QuantifiedNot AvailableNot AvailableTaking drug identified by DrugBank entry DB00973 details
UrineExpected but not QuantifiedNot QuantifiedNot AvailableNot AvailableTaking drug identified by DrugBank entry DB00973 details
Abnormal Concentrations
Not Available
Associated Disorders and Diseases
Disease ReferencesNone
Associated OMIM IDsNone
DrugBank IDDB00973
Phenol Explorer Compound IDNot Available
FooDB IDNot Available
KNApSAcK IDNot Available
Chemspider ID132493
KEGG Compound IDNot Available
BioCyc IDNot Available
BiGG IDNot Available
Wikipedia LinkEzetimibe
METLIN IDNot Available
PubChem Compound150311
PDB IDNot Available
ChEBI ID49040
Food Biomarker OntologyNot Available
VMH IDNot Available
MarkerDB ID
References
Synthesis ReferenceNot Available
Material Safety Data Sheet (MSDS)Not Available
General References
  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:15928087 ]

Only showing the first 10 proteins. There are 11 proteins in total.

Enzymes

General function:
Involved in proteolysis
Specific function:
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, responsible for the processing of peptide hormones, such as angiotensin III and IV, neuropeptides, and chemokines. 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.
Gene Name:
ANPEP
Uniprot ID:
P15144
Molecular weight:
Not Available
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:15494415 ]
General function:
Involved in transferase activity, transferring hexosyl groups
Specific function:
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. 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. Is also active with androsterone, hyodeoxycholic acid and tetrachlorocatechol (in vitro).
Gene Name:
UGT2B7
Uniprot ID:
P16662
Molecular weight:
60720.15
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:14977865 ]
  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:15871634 ]
General function:
Involved in transferase activity, transferring hexosyl groups
Specific function:
UDPGTs are of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isozyme displays activity toward several classes of xenobiotic substrates, including simple phenolic compounds, 7-hydroxylated coumarins, flavonoids, anthraquinones, and certain drugs and their hydroxylated metabolites. It also catalyzes the glucuronidation of endogenous estrogens and androgens.
Gene Name:
UGT2B15
Uniprot ID:
P54855
Molecular weight:
61035.815
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:14977865 ]
  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:15871634 ]
General function:
Involved in transferase activity, transferring hexosyl groups
Specific function:
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. Is also able to catalyze the glucuronidation of 17beta-estradiol, 17alpha-ethinylestradiol, 1-hydroxypyrene, 4-methylumbelliferone, 1-naphthol, paranitrophenol, scopoletin, and umbelliferone.
Gene Name:
UGT1A1
Uniprot ID:
P22309
Molecular weight:
59590.91
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. doi: 10.1038/clpt.2011.4. Epub 2011 Mar 2. [PubMed:21368751 ]
  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:15871634 ]
General function:
Involved in transferase activity, transferring hexosyl groups
Specific function:
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds.
Gene Name:
UGT1A3
Uniprot ID:
P35503
Molecular weight:
60337.835
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. doi: 10.1038/clpt.2011.4. Epub 2011 Mar 2. [PubMed:21368751 ]
  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:15871634 ]
General function:
Involved in acyl-CoA binding
Specific function:
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.
Gene Name:
SOAT1
Uniprot ID:
P35610
Molecular weight:
58130.665
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. doi: 10.1007/s10295-009-0622-z. Epub 2009 Aug 8. [PubMed:19669185 ]
  2. Costet P: Molecular pathways and agents for lowering LDL-cholesterol in addition to statins. Pharmacol Ther. 2010 Jun;126(3):263-78. doi: 10.1016/j.pharmthera.2010.02.006. Epub 2010 Mar 19. [PubMed:20227438 ]
  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. doi: 10.1053/j.gastro.2008.03.011. Epub 2008 Mar 10. [PubMed:18442485 ]
General function:
Involved in monooxygenase activity
Specific function:
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. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide.
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular weight:
57255.585
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:15871634 ]
General function:
Involved in cholesterol transport
Specific function:
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
Gene Name:
NPC1L1
Uniprot ID:
Q9UHC9
Molecular weight:
148696.5
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:14976318 ]
  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:15679830 ]
  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:15737409 ]
  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:15928087 ]
  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:15992510 ]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]

Transporters

General function:
Involved in transporter activity
Specific function:
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
Gene Name:
SLCO1B1
Uniprot ID:
Q9Y6L6
Molecular weight:
76448.0
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. doi: 10.1038/clpt.2011.4. Epub 2011 Mar 2. [PubMed:21368751 ]
General function:
Involved in ATP binding
Specific function:
Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter
Gene Name:
ABCC2
Uniprot ID:
Q92887
Molecular weight:
174205.6
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. doi: 10.1038/clpt.2011.4. Epub 2011 Mar 2. [PubMed:21368751 ]
General function:
Involved in ATP binding
Specific function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular weight:
141477.3
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. doi: 10.1038/clpt.2011.4. Epub 2011 Mar 2. [PubMed:21368751 ]

Only showing the first 10 proteins. There are 11 proteins in total.