Details of the Drug

General Information of Drug (ID: DMH07Y3)

Drug Name

Letrozole

Synonyms

Femara; Femera; Letoval; Letrozol; Novartis Brand of Letrozole; CGS 20267; CGS-20267; FEM-345; Femara (TN); Letrozole [USAN:INN]; CGS 20267, Femara, Piroxicam, Letrozole; Letrozole (JAN/USP/INN); 1-[Bis-(4-cyanophenyl)methyl]-1,2,4-triazole; 1-[bis(4-cyanophenyl)methyl]-1,2,4-triazole; 4,4'-((1h-1,2,4-triazol-1-yl)methylene)dibenzonitrile; 4,4'-(1H-1,2,4-Triazol-1-ylmethylene)dibenzonitrile; 4,4'-(1H-1,2,4-triazol-1-yl-methylene)-bis(benzonitrile); 4,4'-(1H-1,2,4-triazol-1-ylmethanediyl)dibenzonitrile; 4,4'-(1H-1,2,4-triazol-1-ylmethylene)bis-Benzonitrile Letrozole; 4,4'-(1h-1,2,4-triazol-1-ylmethylene) bis-benzonitrile; 4,4'-(1h-1,2,4-triazol-1-ylmethylene)bis-benzonitrile; 4,4'-(1h-1,2,4-triazol-1-ylmethylene)bisbenzonitrile; 4-[(4-cyanophenyl)-(1,2,4-triazol-1-yl)methyl]benzonitrile

Indication

Disease Entry	ICD 11	Status	REF
Estrogen-receptor positive breast cancer	N.A.	Approved	[1]
Hormonally-responsive breast cancer	2C60-2C65	Approved	[2]
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Therapeutic Class

Anticancer Agents

Affected Organisms

Humans and other mammals

ATC Code

L02BG04: Letrozole

L02BG: Aromatase inhibitors

L02B: HORMONE ANTAGONISTS AND RELATED AGENTS

L02: ENDOCRINE THERAPY

L: ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Type

Small molecular drug

Structure

3D MOL

2D MOL

#Ro5 Violations (Lipinski): 0

Molecular Weight (mw)

285.3

Logarithm of the Partition Coefficient (xlogp)

2.7

Rotatable Bond Count (rotbonds)

Hydrogen Bond Donor Count (hbonddonor)

Hydrogen Bond Acceptor Count (hbondacc)

ADMET Property

Absorption Cmax: The maximum plasma concentration (Cmax) of drug is 0.104 micromol/L [3]
Absorption Tmax: The time to maximum plasma concentration (Tmax) is 8.1 h [3]
BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 1: high solubility and high permeability [4]
Bioavailability: The bioavailability of drug is 99.9% [3]
Clearance: The clearance of drug is 1.52 L/h [5]
Elimination: Letrozole is 90% eliminated in the urine [6]
Half-life: The concentration or amount of drug in body reduced by one-half in 42 hours [3]
Metabolism: The drug is metabolized via the CYP2A6 to a ketone analog metabolite and further metabolized by CYP3A4 and CYP2A6 to 4,4'-(hydroxymethylene)dibenzonitrile []
MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 0.14616 micromolar/kg/day [7]
Unbound Fraction: The unbound fraction of drug in plasma is 0.41% [8]
Vd: The volume of distribution (Vd) of drug is 1.87 L/kg [3]
Water Solubility: The ability of drug to dissolve in water is measured as 0.041 mg/mL [4]

Adverse Drug Reaction (ADR)

ADR Term	Variation	Related DOT	DOT ID	REF
Cardiovascular disorder	Not Available	AK1	OT614AR3	[9]
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Chemical Identifiers

Formula: C17H11N5
IUPAC Name: 4-[(4-cyanophenyl)-(1,2,4-triazol-1-yl)methyl]benzonitrile
Canonical SMILES: C1=CC(=CC=C1C#N)C(C2=CC=C(C=C2)C#N)N3C=NC=N3
InChI: InChI=1S/C17H11N5/c18-9-13-1-5-15(6-2-13)17(22-12-20-11-21-22)16-7-3-14(10-19)4-8-16/h1-8,11-12,17H
InChIKey: HPJKCIUCZWXJDR-UHFFFAOYSA-N

Cross-matching ID

PubChem CID: 3902
ChEBI ID: CHEBI:6413
CAS Number: 112809-51-5
UNII: 7LKK855W8I
DrugBank ID: DB01006
TTD ID: D0C1WH
INTEDE ID: DR0929
ACDINA ID: D00356

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
Aromatase (CYP19A1)	TTSZLWK	CP19A_HUMAN	Inhibitor	[10]

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Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Substrate	[11]
Cytochrome P450 2A6 (CYP2A6)_{Main DME}	DEJVYAZ	CP2A6_HUMAN	Substrate	[12]
Aromatase (CYP19A1)	DEQX145	CP19A_HUMAN	Substrate	[13]

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Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Adenylate kinase isoenzyme 1 (AK1)	OT614AR3	KAD1_HUMAN	Drug Response	[9]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Gene/Protein Processing	[14]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Gene/Protein Processing	[15]
Cytochrome P450 2A6 (CYP2A6)	OT52TWG3	CP2A6_HUMAN	Biotransformations	[16]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Biotransformations	[16]
Dickkopf-related protein 1 (DKK1)	OTRDLUSP	DKK1_HUMAN	Gene/Protein Processing	[17]
Fibroblast growth factor 22 (FGF22)	OTVIX6J0	FGF22_HUMAN	Gene/Protein Processing	[17]
Follitropin subunit beta (FSHB)	OTGLS283	FSHB_HUMAN	Gene/Protein Processing	[18]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Gene/Protein Processing	[19]
G1/S-specific cyclin-D2 (CCND2)	OTDULQF9	CCND2_HUMAN	Gene/Protein Processing	[19]

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Molecular Interaction Atlas (MIA)

MIA Detail

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Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Same Disease as Letrozole

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Disease	REF
Lapatinib	DM3BH1Y	Moderate	Decreased metabolism of Letrozole caused by Lapatinib mediated inhibition of CYP450 enzyme.	Breast cancer [2C60-2C6Y]	[20]
Tucatinib	DMBESUA	Moderate	Decreased metabolism of Letrozole caused by Tucatinib mediated inhibition of CYP450 enzyme.	Breast cancer [2C60-2C6Y]	[21]
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Coadministration of a Drug Treating the Disease Different from Letrozole (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Arn-509	DMT81LZ	Moderate	Increased metabolism of Letrozole caused by Arn-509 mediated induction of CYP450 enzyme.	Acute myeloid leukaemia [2A60]	[22]
Dronedarone	DMA8FS5	Moderate	Decreased metabolism of Letrozole caused by Dronedarone mediated inhibition of CYP450 enzyme.	Angina pectoris [BA40]	[23]
Cilostazol	DMZMSCT	Moderate	Decreased metabolism of Letrozole caused by Cilostazol mediated inhibition of CYP450 enzyme.	Arterial occlusive disease [BD40]	[24]
Ivacaftor	DMZC1HS	Moderate	Decreased metabolism of Letrozole caused by Ivacaftor mediated inhibition of CYP450 enzyme.	Cystic fibrosis [CA25]	[25]
MK-8228	DMOB58Q	Moderate	Decreased metabolism of Letrozole caused by MK-8228 mediated inhibition of CYP450 enzyme.	Cytomegaloviral disease [1D82]	[26]
Escitalopram	DMFK9HG	Moderate	Decreased metabolism of Letrozole caused by Escitalopram mediated inhibition of CYP450 enzyme.	Depression [6A70-6A7Z]	[27]
Cenobamate	DM8KLU9	Moderate	Increased metabolism of Letrozole caused by Cenobamate mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[28]
Brivaracetam	DMSEPK8	Minor	Decreased metabolism of Letrozole caused by Brivaracetam mediated inhibition of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[22]
Rufinamide	DMWE60C	Moderate	Increased metabolism of Letrozole caused by Rufinamide mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[22]
Phenobarbital	DMXZOCG	Minor	Decreased metabolism of Letrozole caused by Phenobarbital mediated inhibition of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[29]
Cannabidiol	DM0659E	Minor	Decreased metabolism of Letrozole caused by Cannabidiol mediated inhibition of CYP450 enzyme.	Epileptic encephalopathy [8A62]	[22]
Boceprevir	DMBSHMF	Moderate	Decreased metabolism of Letrozole caused by Boceprevir mediated inhibition of CYP450 enzyme.	Hepatitis virus infection [1E50-1E51]	[30]
Telaprevir	DMMRV29	Moderate	Decreased metabolism of Letrozole caused by Telaprevir mediated inhibition of CYP450 enzyme.	Hepatitis virus infection [1E50-1E51]	[31]
Rifapentine	DMCHV4I	Moderate	Increased metabolism of Letrozole caused by Rifapentine mediated induction of CYP450 enzyme.	HIV-infected patients with tuberculosis [1B10-1B14]	[32]
Etravirine	DMGV8QU	Moderate	Increased metabolism of Letrozole caused by Etravirine mediated induction of CYP450 enzyme.	Human immunodeficiency virus disease [1C60-1C62]	[33]
Darunavir	DMN3GCH	Moderate	Decreased metabolism of Letrozole caused by Darunavir mediated inhibition of CYP450 enzyme.	Human immunodeficiency virus disease [1C60-1C62]	[34]
Pirfenidone	DM6VZFQ	Moderate	Decreased metabolism of Letrozole caused by Pirfenidone mediated inhibition of CYP450 enzyme.	Idiopathic interstitial pneumonitis [CB03]	[22]
Brigatinib	DM7W94S	Moderate	Increased metabolism of Letrozole caused by Brigatinib mediated induction of CYP450 enzyme.	Lung cancer [2C25]	[35]
Ceritinib	DMB920Z	Moderate	Decreased metabolism of Letrozole caused by Ceritinib mediated inhibition of CYP450 enzyme.	Lung cancer [2C25]	[36]
PF-06463922	DMKM7EW	Moderate	Increased metabolism of Letrozole caused by PF-06463922 mediated induction of CYP450 enzyme.	Lung cancer [2C25]	[37]
Selpercatinib	DMZR15V	Moderate	Decreased metabolism of Letrozole caused by Selpercatinib mediated inhibition of CYP450 enzyme.	Lung cancer [2C25]	[22]
Idelalisib	DM602WT	Moderate	Decreased metabolism of Letrozole caused by Idelalisib mediated inhibition of CYP450 enzyme.	Mature B-cell leukaemia [2A82]	[38]
IPI-145	DMWA24P	Moderate	Decreased metabolism of Letrozole caused by IPI-145 mediated inhibition of CYP450 enzyme.	Mature B-cell leukaemia [2A82]	[39]
Dabrafenib	DMX6OE3	Moderate	Increased metabolism of Letrozole caused by Dabrafenib mediated induction of CYP450 enzyme.	Melanoma [2C30]	[22]
Exjade	DMHPRWG	Moderate	Decreased metabolism of Letrozole caused by Exjade mediated inhibition of CYP450 enzyme.	Mineral absorption/transport disorder [5C64]	[40]
Flibanserin	DM70DTN	Moderate	Decreased metabolism of Letrozole caused by Flibanserin mediated inhibition of CYP450 enzyme.	Mood disorder [6A60-6E23]	[41]
Thalidomide	DM70BU5	Major	Additive thrombogenic effects by the combination of Letrozole and Thalidomide.	Multiple myeloma [2A83]	[42]
Fedratinib	DM4ZBK6	Moderate	Decreased metabolism of Letrozole caused by Fedratinib mediated inhibition of CYP450 enzyme.	Myeloproliferative neoplasm [2A20]	[22]
Nilotinib	DM7HXWT	Moderate	Decreased metabolism of Letrozole caused by Nilotinib mediated inhibition of CYP450 enzyme.	Myeloproliferative neoplasm [2A20]	[43]
Dasatinib	DMJV2EK	Moderate	Decreased metabolism of Letrozole caused by Dasatinib mediated inhibition of CYP450 enzyme.	Myeloproliferative neoplasm [2A20]	[44]
Omacetaxine mepesuccinate	DMPU2WX	Moderate	Additive myelosuppressive effects by the combination of Letrozole and Omacetaxine mepesuccinate.	Myeloproliferative neoplasm [2A20]	[45]
Rucaparib	DM9PVX8	Moderate	Decreased metabolism of Letrozole caused by Rucaparib mediated inhibition of CYP450 enzyme.	Ovarian cancer [2C73]	[46]
Abametapir	DM2RX0I	Moderate	Decreased metabolism of Letrozole caused by Abametapir mediated inhibition of CYP450 enzyme.	Pediculosis [1G00]	[47]
Lefamulin	DME6G97	Moderate	Decreased metabolism of Letrozole caused by Lefamulin mediated inhibition of CYP450 enzyme.	Pneumonia [CA40]	[48]
Lonafarnib	DMGM2Z6	Moderate	Decreased metabolism of Letrozole caused by Lonafarnib mediated inhibition of CYP450 enzyme.	Premature ageing appearance [LD2B]	[49]
Enzalutamide	DMGL19D	Moderate	Increased metabolism of Letrozole caused by Enzalutamide mediated induction of CYP450 enzyme.	Prostate cancer [2C82]	[50]
Temsirolimus	DMS104F	Moderate	Increased plasma concentrations of Letrozole and Temsirolimus due to competitive inhibition of the same metabolic pathway.	Renal cell carcinoma [2C90]	[51]
Telotristat ethyl	DMDIYFZ	Moderate	Increased metabolism of Letrozole caused by Telotristat ethyl mediated induction of CYP450 enzyme.	Small intestine developmental anomaly [DA90]	[22]
Larotrectinib	DM26CQR	Moderate	Decreased metabolism of Letrozole caused by Larotrectinib mediated inhibition of CYP450 enzyme.	Solid tumour/cancer [2A00-2F9Z]	[36]
Armodafinil	DMGB035	Minor	Increased metabolism of Letrozole caused by Armodafinil mediated induction of CYP450 enzyme.	Solid tumour/cancer [2A00-2F9Z]	[52]
LEE011	DMMX75K	Moderate	Decreased metabolism of Letrozole caused by LEE011 mediated inhibition of CYP450 enzyme.	Solid tumour/cancer [2A00-2F9Z]	[53]
Pitolisant	DM8RFNJ	Moderate	Increased metabolism of Letrozole caused by Pitolisant mediated induction of CYP450 enzyme.	Somnolence [MG42]	[22]
Fostamatinib	DM6AUHV	Moderate	Decreased metabolism of Letrozole caused by Fostamatinib mediated inhibition of CYP450 enzyme.	Thrombocytopenia [3B64]	[54]
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Drug Inactive Ingredient(s) (DIG) and Formulation(s) of This Drug

DIG

DIG Name	DIG ID	PubChem CID	Functional Classification
Allura red AC dye	E00338	33258	Colorant
D&C red no. 27	E00381	83511	Colorant
FD&C blue no. 2	E00446	2723854	Colorant
Hydrazine yellow	E00409	164825	Colorant
Mannitol	E00103	6251	Diluent; Flavoring agent; Lyophilization aid; Plasticizing agent; Tonicity agent
Sodium lauryl sulfate	E00464	3423265	Emulsifying agent; Modified-release agent; Penetration agent; Solubilizing agent; Surfactant; lubricant
Sunset yellow FCF	E00255	17730	Colorant
Beta-D-lactose	E00099	6134	Diluent; Dry powder inhaler carrier; Lyophilization aid
Carmellose sodium	E00625	Not Available	Disintegrant
Eisenoxyd	E00585	56841934	Colorant
Ferric hydroxide oxide yellow	E00539	23320441	Colorant
Ferrosoferric oxide	E00231	14789	Colorant
Lactose monohydrate	E00393	104938	Binding agent; Diluent; Dry powder inhaler carrier; Lyophilization aid
Magnesium stearate	E00208	11177	lubricant
Polyethylene glycol 3350	E00652	Not Available	Coating agent; Diluent; Ointment base; Plasticizing agent; Solvent; Suppository base; lubricant
Polyethylene glycol 400	E00653	Not Available	Coating agent; Diluent; Ointment base; Plasticizing agent; Solvent; Suppository base; lubricant
Polyethylene glycol 4000	E00654	Not Available	Coating agent; Diluent; Ointment base; Plasticizing agent; Solvent; Suppository base; lubricant
Polyvinyl alcohol	E00666	Not Available	Coating agent; Emulsion stabilizing agent; Film/Membrane-forming agent
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
Talc	E00520	16211421	Anticaking agent; Diluent; Glidant; lubricant
Titanium dioxide	E00322	26042	Coating agent; Colorant; Opacifying agent
Triacetin	E00080	5541	Humectant; Plasticizing agent; Solvent
Vinylpyrrolidone	E00668	Not Available	Binding agent; Coating agent; Disintegrant; Film/membrane-forming agent; Solubilizing agent; Suspending agent
Water	E00035	962	Solvent
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⏷ Show the Full List of 25 Pharmaceutical Excipients of This Drug

Pharmaceutical Formulation

Formulation Name	Drug Dosage	Dosage Form	Route
Letrozole 2.5 mg tablet	2.5 mg	Oral Tablet	Oral

Jump to Detail Pharmaceutical Formulation Page of This Drug

References

1	Letrozole 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: 5209).
3	The discovery and mechanism of action of letrozole. Breast Cancer Res Treat. 2007;105 Suppl 1:7-17. doi: 10.1007/s10549-007-9696-3. Epub 2007 Oct 3.
4	BDDCS applied to over 900 drugs
5	Pfister CU, Martoni A, Zamagni C, Lelli G, De Braud F, Souppart C, Duval M, Hornberger U: Effect of age and single versus multiple dose pharmacokinetics of letrozole (Femara) in breast cancer patients. Biopharm Drug Dispos. 2001 Jul;22(5):191-7. doi: 10.1002/bdd.273.
6	FDA Approved Drug Products: Femara Letrozole Oral Tablets
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	Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
9	ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
10	Aromatase inhibitors--theoretical concept and present experiences in the treatment of endometriosis. Zentralbl Gynakol. 2003 Jul-Aug;125(7-8):247-51.
11	Inhibition of drug metabolizing cytochrome P450s by the aromatase inhibitor drug letrozole and its major oxidative metabolite 4,4'-methanol-bisbenzonitrile in vitro. Cancer Chemother Pharmacol. 2009 Oct;64(5):867-75.
12	Letrozole concentration is associated with CYP2A6 variation but not with arthralgia in patients with breast cancer. Breast Cancer Res Treat. 2018 Nov;172(2):371-379.
13	Double-blind, randomised, multicentre endocrine trial comparing two letrozole doses, in postmenopausal breast cancer patients. Eur J Cancer. 1999 Feb;35(2):208-13.
14	Aromatase inhibition: translation into a successful therapeutic approach. Clin Cancer Res. 2005 Apr 15;11(8):2809-21. doi: 10.1158/1078-0432.CCR-04-2187.
15	Synergistic activity of letrozole and sorafenib on breast cancer cells. Breast Cancer Res Treat. 2010 Nov;124(1):79-88. doi: 10.1007/s10549-009-0714-5. Epub 2010 Jan 7.
16	Deactivation of anti-cancer drug letrozole to a carbinol metabolite by polymorphic cytochrome P450 2A6 in human liver microsomes. Xenobiotica. 2009 Nov;39(11):795-802. doi: 10.3109/00498250903171395.
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49	Product Information. Zokinvy (lonafarnib). Eiger BioPharmaceuticals, Palo Alto, CA.
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