Details of the Drug

General Information of Drug (ID: DM7A8TW)

Drug Name

Ezetimibe

Synonyms

Ezedoc; Ezetimib; Ezetrol; Zetia; Zient; Essex brand of ezetimibe; MSD brand of ezetimibe; Merck brand of ezetimibe; SCH58235; Sch 58235; Ezetimibe [USAN:INN]; Inegy (TN); MK-0653; SCH-58235; Schering-Plough brand of ezetimibe; Vytorin (TN); Zetia (TN); Zetia , Ezetrol, Ezetimibe; Ezetimibe (JAN/USAN/INN); (-)-Sch 58235; (1-(4-fluorophenyl)-(3R)-(3-(4-fluorophenyl)-(3S)-hydroxypropyl)-(4S)-(4-hydroxyphenyl)-2-azetidinone); (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one; (3R,4S)-1-(p-Fluorophenyl)-3-((3S)-3-(p-fluorophenyl)-3-hydroxypropyl)-4-(p-hydroxyphenyl)-2-azetidinone; 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-(4-hydroxyphenyl)-2-azetidione; 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone

Indication

Disease Entry	ICD 11	Status	REF
Atherosclerosis	BD40	Approved	[1]
Hypercholesterolaemia	5C80.0	Approved	[2]
Hyperlipidemia	5C80.Z	Approved	[1]
Hyperlipidemia, familial combined, LPL related	N.A.	Approved	[1]
Non-alcoholic fatty liver disease	DB92	Approved	[1]
Type-1/2 diabetes	5A10-5A11	Approved	[1]
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Therapeutic Class

Anticholesteremic Agents

Drug Type

Small molecular drug

Structure

3D MOL

2D MOL

#Ro5 Violations (Lipinski): 0

Molecular Weight (mw)

409.4

Logarithm of the Partition Coefficient (xlogp)

4

Rotatable Bond Count (rotbonds)

6

Hydrogen Bond Donor Count (hbonddonor)

2

Hydrogen Bond Acceptor Count (hbondacc)

5

ADMET Property

Absorption Tmax: The time to maximum plasma concentration (Tmax) is 0.3-1 h [3]
BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 2: low solubility and high permeability [4]
Bioavailability: The bioavailability of drug is 56% [3]
Elimination: Approximately 78% and 11% of orally administered radiolabelled ezetimibe are recovered in the feces and urine, respectively [5]
Half-life: The concentration or amount of drug in body reduced by one-half in 22 hours [5]
Metabolism: The drug is metabolized via a phase II glucuronide conjugation reaction in the small intestine and liver to form its main phenolic metabolite ezetimibe glucuronide [6]
MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 0.3489 micromolar/kg/day [7]
Vd: The volume of distribution (Vd) of drug is 107.5 L []

Chemical Identifiers

Formula: C24H21F2NO3
IUPAC Name: (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one
Canonical SMILES: C1=CC(=CC=C1[C@@H]2[C@H](C(=O)N2C3=CC=C(C=C3)F)CC[C@@H](C4=CC=C(C=C4)F)O)O
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
InChIKey: OLNTVTPDXPETLC-XPWALMASSA-N

Cross-matching ID

PubChem CID: 150311
ChEBI ID: CHEBI:49040
CAS Number: 163222-33-1
DrugBank ID: DB00973
TTD ID: D09LWS
VARIDT ID: DR00140
INTEDE ID: DR0677
ACDINA ID: D00262

Combinatorial Drugs (CBD)

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Repurposed Drugs (RPD)

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Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Niemann-Pick C1-like protein 1 (NPC1L1)	TTPD1CN	NPCL1_HUMAN	Inhibitor	[8]

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Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
Bile salt export pump (ABCB11)	DTJ0EW4	ABCBB_HUMAN	Substrate	[9]
Multidrug resistance-associated protein 3 (ABCC3)	DTQ3ZHF	MRP3_HUMAN	Substrate	[10]
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[11]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[10]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[12]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[13]

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Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Substrate	[14]
UDP-glucuronosyltransferase 1A1 (UGT1A1)_{Main DME}	DEYGVN4	UD11_HUMAN	Substrate	[14]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Substrate	[14]
UDP-glucuronosyltransferase 1A3 (UGT1A3)_{Main DME}	DEF2WXN	UD13_HUMAN	Substrate	[15]
UDP-glucuronosyltransferase 2B15 (UGT2B15)_{Main DME}	DENZ6B1	UDB15_HUMAN	Substrate	[14]

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Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)	OTRT3F3U	HMDH_HUMAN	Gene/Protein Processing	[16]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Gene/Protein Processing	[9]
NPC1-like intracellular cholesterol transporter 1 (NPC1L1)	OT6GWW1P	NPCL1_HUMAN	Drug Response	[17]
Oxysterols receptor LXR-beta (NR1H2)	OT4APA60	NR1H2_HUMAN	Gene/Protein Processing	[18]
Phospholipid-transporting ATPase ABCA1 (ABCA1)	OT94G6BQ	ABCA1_HUMAN	Gene/Protein Processing	[18]
Retinoic acid receptor gamma (RARG)	OT8LHMDH	RARG_HUMAN	Gene/Protein Processing	[18]
Scavenger receptor class B member 1 (SCARB1)	OTAE1UA1	SCRB1_HUMAN	Gene/Protein Processing	[18]
Sterol regulatory element-binding protein 1 (SREBF1)	OTWBRPAI	SRBP1_HUMAN	Gene/Protein Processing	[18]
Sterol regulatory element-binding protein 2 (SREBF2)	OTBXUNPL	SRBP2_HUMAN	Gene/Protein Processing	[18]
UDP-glucuronosyltransferase 1A1	OTH1C8OJ	UD11_HUMAN	Biotransformations	[19]

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Molecular Interaction Atlas (MIA)

MIA Detail

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Molecular Expression Atlas of This Drug

The Studied Disease

Atherosclerosis

ICD Disease Classification

BD40

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Niemann-Pick C1-like protein 1 (NPC1L1)	DTT	NPC1L1	1.75E-01	-0.05	-0.27
P-glycoprotein 1 (ABCB1)	DTP	P-GP	3.29E-14	-7.08E-01	-1.99E+00
Multidrug resistance-associated protein 3 (ABCC3)	DTP	MRP3	5.09E-05	4.90E-01	1.66E+00
Bile salt export pump (ABCB11)	DTP	BSEP	2.41E-01	-3.08E-02	-2.35E-01
Breast cancer resistance protein (ABCG2)	DTP	BCRP	2.28E-08	-3.66E-01	-8.07E-01
Multidrug resistance-associated protein 2 (ABCC2)	DTP	MRP2	4.30E-02	-2.29E-01	-9.10E-01
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DTP	OATP1B1	3.27E-01	-5.78E-02	-3.84E-01
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DME	UGT1A1	2.00E-01	5.79E-02	3.00E-01
UDP-glucuronosyltransferase 2B15 (UGT2B15)	DME	UGT2B15	1.87E-01	-5.07E-03	-2.38E-02
Cytochrome P450 3A4 (CYP3A4)	DME	CYP3A4	3.24E-05	-3.48E-01	-1.34E+00

Molecular Expression Atlas (MEA)

MEA Detail

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Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Ezetimibe (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Midostaurin	DMI6E0R	Moderate	Decreased clearance of Ezetimibe due to the transporter inhibition by Midostaurin.	Acute myeloid leukaemia [2A60]	[20]
Arn-509	DMT81LZ	Moderate	Accelerated clearance of Ezetimibe due to the transporter induction by Arn-509.	Acute myeloid leukaemia [2A60]	[20]
Ag-221	DMS0ZBI	Moderate	Decreased clearance of Ezetimibe due to the transporter inhibition by Ag-221.	BCR-ABL1-negative chronic myeloid leukaemia [2A41]	[21]
Fostemsavir	DM50ILT	Moderate	Decreased clearance of Ezetimibe due to the transporter inhibition by Fostemsavir.	Human immunodeficiency virus disease [1C60-1C62]	[22]
Darolutamide	DMV7YFT	Moderate	Decreased clearance of Ezetimibe due to the transporter inhibition by Darolutamide.	Prostate cancer [2C82]	[20]
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Drug Inactive Ingredient(s) (DIG) and Formulation(s) of This Drug

DIG

DIG Name	DIG ID	PubChem CID	Functional Classification
Sodium lauryl sulfate	E00464	3423265	Emulsifying agent; Modified-release agent; Penetration agent; Solubilizing agent; Surfactant; lubricant
Sodium stearyl fumarate	E00545	23665634	lubricant
Carmellose sodium	E00625	Not Available	Disintegrant
Crospovidone	E00626	Not Available	Disintegrant
Lactose monohydrate	E00393	104938	Binding agent; Diluent; Dry powder inhaler carrier; Lyophilization aid
Magnesium stearate	E00208	11177	lubricant
Povidone	E00667	Not Available	Binding agent; Coating agent; Disintegrant; Film/membrane-forming agent; Solubilizing agent; Suspending agent
Silicon dioxide	E00670	Not Available	Anticaking agent; Opacifying agent; Viscosity-controlling agent
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Pharmaceutical Formulation

Formulation Name	Drug Dosage	Dosage Form	Route
Ezetimibe 10 mg tablet	10 mg	Oral Tablet	Oral

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References

1	Ezetimibe FDA Label
2	URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6816).
3	Monamine Oxidase Inhibitors
4	BDDCS applied to over 900 drugs
5	FDA Approved Drug Products: Zetia (ezetimibe) oral tablets
6	Reeves PR, McAinsh J, McIntosh DA, Winrow MJ: Metabolism of atenolol in man. Xenobiotica. 1978 May;8(5):313-20. doi: 10.3109/00498257809060956.
7	Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
8	Update on patented cholesterol absorption inhibitors. Expert Opin Ther Pat. 2009 Aug;19(8):1083-107.
9	Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
10	Complex pharmacokinetic behavior of ezetimibe depends on abcc2, abcc3, and abcg2. Drug Metab Dispos. 2009 Aug;37(8):1698-702.
11	Intestinal expression of P-glycoprotein (ABCB1), multidrug resistance associated protein 2 (ABCC2), and uridine diphosphate-glucuronosyltransferase 1A1 predicts the disposition and modulates the effects of the cholesterol absorption inhibitor ezetimibe in humans. Clin Pharmacol Ther. 2006 Mar;79(3):206-17.
12	A LC-MS/MS method to quantify the novel cholesterol lowering drug ezetimibe in human serum, urine and feces in healthy subjects genotyped for SLCO1B1. J Chromatogr B Analyt Technol Biomed Life Sci. 2006 Jan 2;830(1):143-50.
13	Pharmacokinetic and pharmacodynamic interactions between the immunosuppressant sirolimus and the lipid-lowering drug ezetimibe in healthy volunteers. Clin Pharmacol Ther. 2010 Jun;87(6):663-7.
14	Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clin Pharmacokinet. 2005;44(5):467-94.
15	Drug interactions between the immunosuppressant tacrolimus and the cholesterol absorption inhibitor ezetimibe in healthy volunteers. Clin Pharmacol Ther. 2011 Apr;89(4):524-8.
16	Effects of ezetimibe and/or simvastatin on LDL receptor protein expression and on LDL receptor and HMG-CoA reductase gene expression: a randomized trial in healthy men. Atherosclerosis. 2008 May;198(1):198-207.
17	Compound heterozygosity for two non-synonymous polymorphisms in NPC1L1 in a non-responder to ezetimibe. Clin Genet. 2005 Feb;67(2):175-7. doi: 10.1111/j.1399-0004.2004.00388.x.
18	Carotenoid transport is decreased and expression of the lipid transporters SR-BI, NPC1L1, and ABCA1 is downregulated in Caco-2 cells treated with ezetimibe. J Nutr. 2005 Oct;135(10):2305-12. doi: 10.1093/jn/135.10.2305.
19	Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of ezetimibe (Zetia). Drug Metab Dispos. 2004 Mar;32(3):314-20.
20	Cerner Multum, Inc. "UK Summary of Product Characteristics.".
21	Cerner Multum, Inc. "Australian Product Information.".
22	Product Information. Rukobia (fostemsavir). ViiV Healthcare, Research Triangle Park, NC.