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Identification
- Summary
Letrozole is an aromatase inhibitor used to treat breast cancer in postmenopausal women.
- Brand Names
- Femara, Kisqali Femara Co-pack
- Generic Name
- Letrozole
- DrugBank Accession Number
- DB01006
- Background
Letrozole, or CGS 20267, is an oral non-steroidal type II aromatase inhibitor first described in the literature in 1990.1,5,9,10 It is a third generation aromatase inhibitor like exemestane and anastrozole, meaning it does not significantly affect cortisol, aldosterone, and thyroxine.2
Letrozole was granted FDA approval on 25 July 1997.9
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Letrozole (DB01006)
- Weight
- Average: 285.3027
Monoisotopic: 285.101445377 - Chemical Formula
- C17H11N5
- Synonyms
- Letrozol
- Letrozole
- External IDs
- CGS 20267
- CGS-20267
Pharmacology
- Indication
Letrozole is indicated to treat postmenopausal women with hormone receptor (HR) positive early breast cancer, postmenopausal women with early breast cancer who have periviously been treated with tamoxifen, and postmenopausal women with HR+ or unknown advanced breast cancer.9 Letrozole, given with ribociclib, is indicated to treat pre, peri, and postmenopausal women with HR+ and human epidermal growth factor 2 (HER2) negative advanced or metastatic breast cancer.10
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Advanced breast cancer •••••••••••• ••••••••••••••• •••••• Treatment of Anovulation ••• ••••• Adjunct therapy in treatment of Early breast cancer •••••••••••• ••••••••••••••• •••••• Treatment of Early breast cancer •••••••••••• •••••••••••••• ••••• ••••••••• ••••••• •••••• Treatment of Epithelial ovarian cancer ••• ••••• - Contraindications & Blackbox Warnings
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Letrozole is an aromatase inhibitor used in the treatment of breast cancer. Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization. As breast tissue is stimulated by estrogens, decreasing their production is a way of suppressing recurrence of the breast tumor tissue.
Letrozole is a third generation type II aromatase inhibitor used to treat estrogen dependant breast cancers.9 It has a long duration of action as it has a half life of over 42 hours in breast cancer patients.2,4,9 Patients should be counselled regarding the risk of interstitial lung disease, pneumonitis, QT prolongation, elevated transaminase levels, neutropenia, and embryo-fetal toxicity.9
- Mechanism of action
Letrozole is a non-steroidal type II aromatase inhibitor.5 It blocks the active site, and therefore the electron transfer chain of CYP19A1.5 This competitive inhibition prevents the conversion of androgens to estrogen.5 This action leads to a reduction in uterine weight and elevated leuteinizing hormone.9 In postmenopausal women, the action of aromatase is responsible for the majority of estrogen production.9 With reduced availability of estrogen, estrogen-dependant tumors regress.9 Third generation aromatase inhibitors do not significantly affect cortisol, aldosterone, and thyroxine levels.2
Target Actions Organism AAromatase antagonistHumans - Absorption
Letrozole is 99.9% orally bioavailable.2 A 2.5mg oral dose reaches a Cmax of 104nmol/L with a Tmax of 8.10h, and an AUC of 7387nmol*h/L.4
- Volume of distribution
The volume of distribution of letrozole is 1.87L/kg.2
- Protein binding
Letrozole is 60% bound to proteins.2,4 55% is bound to albumin.2
- Metabolism
Letrozole is metabolized by CYP2A6 to a ketone analog metabolite, which is further metabolized by CYP3A4 and CYP2A6 to 4,4'-(hydroxymethylene)dibenzonitrile.8 4,4'-(hydroxymethylene)dibenzonitrile is glucuronidated by UGT2B7.3
Hover over products below to view reaction partners
- Route of elimination
Letrozole is 90% eliminated in the urine.9 75% of the dose is recovered as a glucuronide metabolite, 9% is in the form of the ketone and carbinol metabolites, and 6% is recovered in urine as unchanged letrozole.8,9
- Half-life
The terminal elimination half life of letrozole is approximately 42h in healthy volunteers, but longer in breast cancer patients.2,4,9
- Clearance
The average clearance after a single dose of letrozole was 1.52L/h and at steady state was 1.20L/h.4
- Adverse Effects
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Overdose data in humans is not readily available, however 1 reported case was not associated with serious adverse reactions.9 Animal studies do not report serious adverse effects with high dose treatment.6 Patients experiencing and overdose should be treated with symptomatic and supportive measures.9
Oral doses over 2000mg/kg were associated with reduced motor activity, ataxia, dyspnea, and death in mice and rats.9
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Letrozole can be increased when it is combined with Abametapir. Abatacept The metabolism of Letrozole can be increased when combined with Abatacept. Abrocitinib The metabolism of Abrocitinib can be decreased when combined with Letrozole. Acenocoumarol The metabolism of Acenocoumarol can be decreased when combined with Letrozole. Acetaminophen The metabolism of Acetaminophen can be decreased when combined with Letrozole. - Food Interactions
- Take with or without food. Food slows absorption without decreasing the quantity absorbed.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Images
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Co Letrozole Tablet 2.5 mg Oral Cobalt Laboratories Not applicable Not applicable Canada 
Femara Tablet, film coated 2.5 mg/1 Oral Novartis Farma S.P.A. 1997-07-31 Not applicable US 
Femara Tablet, film coated 2.5 mg/1 Oral Physicians Total Care, Inc. 2005-02-10 Not applicable US Femara Tablet 2.5 mg Oral Novartis 1997-09-02 Not applicable Canada Letrozole Tablet 2.5 mg Oral Pro Doc Limitee 2013-02-14 Not applicable Canada - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Accel-letrozole Tablets USP Tablet 2.5 mg / tab Oral Accel Pharma Inc Not applicable Not applicable Canada Ach-letrozole Tablet 2.5 mg Oral Accord Healthcare, S.L.U. 2010-05-03 Not applicable Canada Ag-letrozole Tablet 2.5 mg Oral Angita Pharma Inc. 2022-02-03 Not applicable Canada Ag-letrozole Tablets Tablet 2.5 mg Oral Angita Pharma Inc. 2024-08-20 Not applicable Canada Apo-letrozole Tablet 2.5 mg Oral Apotex Corporation 2012-06-11 Not applicable Canada - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Kisqali Femara Co-pack Letrozole (2.5 mg/1) + Ribociclib succinate (200 mg/1) Kit; Tablet; Tablet, film coated Oral Novartis Farma S.P.A. 2017-05-04 Not applicable US Kisqali Femara Co-pack Letrozole (2.5 mg/1) + Ribociclib succinate (200 mg/1) Kit; Tablet; Tablet, film coated Oral Novartis Farma S.P.A. 2017-05-04 Not applicable US Kisqali Femara Co-pack Letrozole (2.5 mg/1) + Ribociclib succinate (200 mg/1) Kit; Tablet; Tablet, film coated Oral Novartis Farma S.P.A. 2017-05-04 Not applicable US
Categories
- ATC Codes
- L02BG04 — Letrozole
- Drug Categories
- Agents Causing Muscle Toxicity
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Aromatase Inhibitors
- Cytochrome P-450 CYP2A6 Inhibitors
- Cytochrome P-450 CYP2A6 Inhibitors (strong)
- Cytochrome P-450 CYP2A6 Substrates
- Cytochrome P-450 CYP2C19 Inhibitors
- Cytochrome P-450 CYP2C19 inhibitors (strength unknown)
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Endocrine Therapy
- Enzyme Inhibitors
- Estrogen Antagonists
- Hormone Antagonists
- Hormone Antagonists and Related Agents
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Nitriles
- P-glycoprotein substrates
- Steroid Synthesis Inhibitors
- Triazoles
- UGT2B7 substrates
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Diphenylmethanes
- Direct Parent
- Diphenylmethanes
- Alternative Parents
- Benzonitriles / Triazoles / Heteroaromatic compounds / Nitriles / Azacyclic compounds / Organopnictogen compounds / Hydrocarbon derivatives
- Substituents
- 1,2,4-triazole / Aromatic heteromonocyclic compound / Azacycle / Azole / Benzonitrile / Carbonitrile / Diphenylmethane / Heteroaromatic compound / Hydrocarbon derivative / Nitrile
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- nitrile, triazoles (CHEBI:6413)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 7LKK855W8I
- CAS number
- 112809-51-5
- InChI Key
- HPJKCIUCZWXJDR-UHFFFAOYSA-N
- 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
- IUPAC Name
- 4-[(4-cyanophenyl)(1H-1,2,4-triazol-1-yl)methyl]benzonitrile
- SMILES
- N#CC1=CC=C(C=C1)C(N1C=NC=N1)C1=CC=C(C=C1)C#N
References
- Synthesis Reference
Peter MacDonald, Ettore Bigatti, Pierluigi Rossetto, Zvi Harel, "Process for the preparation of letrozole." U.S. Patent US20070066831, issued March 22, 2007.
US20070066831- General References
- Bhatnagar AS, Hausler A, Schieweck K, Lang M, Bowman R: Highly selective inhibition of estrogen biosynthesis by CGS 20267, a new non-steroidal aromatase inhibitor. J Steroid Biochem Mol Biol. 1990 Dec 20;37(6):1021-7. doi: 10.1016/0960-0760(90)90460-3. [Article]
- Bhatnagar AS: 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. [Article]
- Precht JC, Schroth W, Klein K, Brauch H, Krynetskiy E, Schwab M, Murdter TE: The letrozole phase 1 metabolite carbinol as a novel probe drug for UGT2B7. Drug Metab Dispos. 2013 Nov;41(11):1906-13. doi: 10.1124/dmd.113.053405. Epub 2013 Aug 21. [Article]
- 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. [Article]
- Nabholtz JM: Long-term safety of aromatase inhibitors in the treatment of breast cancer. Ther Clin Risk Manag. 2008 Feb;4(1):189-204. [Article]
- Schieweck K, Bhatnagar AS, Batzl C, Lang M: Anti-tumor and endocrine effects of non-steroidal aromatase inhibitors on estrogen-dependent rat mammary tumors. J Steroid Biochem Mol Biol. 1993 Mar;44(4-6):633-6. doi: 10.1016/0960-0760(93)90270-7. [Article]
- Dave N, Chow LM, Gudelsky GA, LaSance K, Qi X, Desai PB: Preclinical pharmacological evaluation of letrozole as a novel treatment for gliomas. Mol Cancer Ther. 2015 Apr;14(4):857-64. doi: 10.1158/1535-7163.MCT-14-0743. Epub 2015 Feb 18. [Article]
- Jeong S, Woo MM, Flockhart DA, Desta Z: 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. doi: 10.1007/s00280-009-0935-7. Epub 2009 Feb 7. [Article]
- FDA Approved Drug Products: Femara Letrozole Oral Tablets [Link]
- FDA Approved Drug Products: Kisquali Femara Co-Pack Letrozole and Ribociclib Succinate Oral Tablets [Link]
- External Links
- Human Metabolome Database
- HMDB0015141
- KEGG Drug
- D00964
- KEGG Compound
- C08163
- PubChem Compound
- 3902
- PubChem Substance
- 46504610
- ChemSpider
- 3765
- BindingDB
- 13061
- 72965
- ChEBI
- 6413
- ChEMBL
- CHEMBL1444
- ZINC
- ZINC000003778874
- Therapeutic Targets Database
- DAP000626
- PharmGKB
- PA450196
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Letrozole
- FDA label
- Download (112 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Active Not Recruiting Not Available Advanced Breast Cancer / Estrogen Receptor Positive Breast Cancer / Human Epidermal Growth Factor 2 Negative Carcinoma of Breast / Luminal Breast Cancer / Metastatic Breast Cancer 1 somestatus stop reason just information to hide Not Available Active Not Recruiting Not Available Breast Cancer 1 somestatus stop reason just information to hide Not Available Active Not Recruiting Not Available Breast Cancer / Malignant Breast Neoplasm 1 somestatus stop reason just information to hide Not Available Completed Not Available Breast Cancer 5 somestatus stop reason just information to hide Not Available Completed Not Available Breast Cancer / Joint Pain / Obesity 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Novartis pharmaceuticals corp
- Mylan pharmaceuticals inc
- Packagers
- Kaiser Foundation Hospital
- Novartis AG
- Physicians Total Care Inc.
- Dosage Forms
Form Route Strength Tablet Oral 2.5 mg / tab Tablet Oral 2.50 mg Tablet Oral Tablet Oral 2.5 MG Tablet, film coated Oral Tablet Oral 250000 mg Kit; tablet; tablet, film coated Oral Tablet, film coated Oral 2.50 mg Tablet, film coated Oral 2.500 mg Tablet, coated Oral 2.5 mg Tablet, coated Oral 250000 mg Tablet Oral 2.5 mg/1 Tablet, coated Oral 2.5 mg/1 Tablet, film coated Oral 2.5 mg/1 Tablet, film coated Oral 2.5 mg Tablet Oral 2.500 mg - Prices
Unit description Cost Unit Femara 2.5 mg tablet 16.87USD tablet DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US4978672 No 1990-12-18 2011-06-03 US US8685980 No 2014-04-01 2030-05-25 US US9193732 No 2015-11-24 2031-11-09 US US8415355 No 2013-04-09 2031-02-19 US US8324225 No 2012-12-04 2028-06-17 US US9416136 No 2016-08-16 2029-08-20 US US8962630 No 2015-02-24 2029-12-09 US US9868739 No 2018-01-16 2031-11-09 US US10799506 No 2020-10-13 2036-04-14 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 184-185 °C FDA Label logP 2.5 Dave N, et al. 2015 - Predicted Properties
Property Value Source Water Solubility 0.0799 mg/mL ALOGPS logP 1.86 ALOGPS logP 2.94 Chemaxon logS -3.6 ALOGPS pKa (Strongest Basic) 1.89 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 78.29 Å2 Chemaxon Rotatable Bond Count 3 Chemaxon Refractivity 94.47 m3·mol-1 Chemaxon Polarizability 29.59 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9965 Blood Brain Barrier + 0.9737 Caco-2 permeable + 0.6347 P-glycoprotein substrate Non-substrate 0.8391 P-glycoprotein inhibitor I Non-inhibitor 0.8087 P-glycoprotein inhibitor II Non-inhibitor 0.9147 Renal organic cation transporter Non-inhibitor 0.5908 CYP450 2C9 substrate Non-substrate 0.7898 CYP450 2D6 substrate Non-substrate 0.9116 CYP450 3A4 substrate Non-substrate 0.6843 CYP450 1A2 substrate Non-inhibitor 0.8374 CYP450 2C9 inhibitor Non-inhibitor 0.9071 CYP450 2D6 inhibitor Non-inhibitor 0.923 CYP450 2C19 inhibitor Inhibitor 0.8993 CYP450 3A4 inhibitor Inhibitor 0.6451 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.7027 Ames test Non AMES toxic 0.6371 Carcinogenicity Non-carcinogens 0.8926 Biodegradation Not ready biodegradable 0.9864 Rat acute toxicity 1.9916 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9261 hERG inhibition (predictor II) Non-inhibitor 0.8817
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 185.7735811 predictedDarkChem Lite v0.1.0 [M-H]- 185.5592811 predictedDarkChem Lite v0.1.0 [M-H]- 185.7594811 predictedDarkChem Lite v0.1.0 [M-H]- 155.9064 predictedDeepCCS 1.0 (2019) [M+H]+ 186.1524811 predictedDarkChem Lite v0.1.0 [M+H]+ 185.8836811 predictedDarkChem Lite v0.1.0 [M+H]+ 186.4743811 predictedDarkChem Lite v0.1.0 [M+H]+ 158.2644 predictedDeepCCS 1.0 (2019) [M+Na]+ 185.9115811 predictedDarkChem Lite v0.1.0 [M+Na]+ 186.3247811 predictedDarkChem Lite v0.1.0 [M+Na]+ 186.2326811 predictedDarkChem Lite v0.1.0 [M+Na]+ 164.3975 predictedDeepCCS 1.0 (2019)
Targets
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Use our structured and evidence-based datasets to unlock newinsights and accelerate drug research.
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- A cytochrome P450 monooxygenase that catalyzes the conversion of C19 androgens, androst-4-ene-3,17-dione (androstenedione) and testosterone to the C18 estrogens, estrone and estradiol, respectively (PubMed:27702664, PubMed:2848247). Catalyzes three successive oxidations of C19 androgens: two conventional oxidations at C19 yielding 19-hydroxy and 19-oxo/19-aldehyde derivatives, followed by a third oxidative aromatization step that involves C1-beta hydrogen abstraction combined with cleavage of the C10-C19 bond to yield a phenolic A ring and formic acid (PubMed:20385561). Alternatively, the third oxidative reaction yields a 19-norsteroid and formic acid. Converts dihydrotestosterone to delta1,10-dehydro 19-nordihydrotestosterone and may play a role in homeostasis of this potent androgen (PubMed:22773874). Also displays 2-hydroxylase activity toward estrone (PubMed:22773874). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:20385561, PubMed:22773874)
- Specific Function
- aromatase activity
- Gene Name
- CYP19A1
- Uniprot ID
- P11511
- Uniprot Name
- Aromatase
- Molecular Weight
- 57882.48 Da
References
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
- Ebert AD, Bartley J, David M, Schweppe KW: [Aromatase inhibitors--theoretical concept and present experiences in the treatment of endometriosis]. Zentralbl Gynakol. 2003 Jul-Aug;125(7-8):247-51. [Article]
- Long BJ, Jelovac D, Handratta V, Thiantanawat A, MacPherson N, Ragaz J, Goloubeva OG, Brodie AM: Therapeutic strategies using the aromatase inhibitor letrozole and tamoxifen in a breast cancer model. J Natl Cancer Inst. 2004 Mar 17;96(6):456-65. [Article]
- Murphy MJ Jr: Molecular Action and Clinical Relevance of Aromatase Inhibitors. Oncologist. 1998;3(2):129-130. [Article]
- FDA Approved Drug Products: Femara Letrozole Oral Tablets [Link]
- FDA Approved Drug Products: Kisquali Femara Co-Pack Letrozole and Ribociclib Succinate Oral Tablets [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates PUFA specifically at the omega-1 position (PubMed:18577768). Catalyzes the epoxidation of double bonds of PUFA (PubMed:19965576, PubMed:20972997). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Hydroxylates fenbendazole at the 4' position (PubMed:23959307)
- Specific Function
- (R)-limonene 6-monooxygenase activity
- Gene Name
- CYP2C19
- Uniprot ID
- P33261
- Uniprot Name
- Cytochrome P450 2C19
- Molecular Weight
- 55944.565 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:10702251, PubMed:15470161, PubMed:15472229, PubMed:17442341, PubMed:18674515, PubMed:18719240, PubMed:19022937, PubMed:23288867, PubMed:23756265, PubMed:26220143). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:15470161, PubMed:18674515, PubMed:23756265). Catalyzes the glucuronidation of endogenous steroid hormones such as androgens (epitestosterone, androsterone) and estrogens (estradiol, epiestradiol, estriol, catechol estrogens) (PubMed:15472229, PubMed:17442341, PubMed:18719240, PubMed:19022937, PubMed:2159463, PubMed:23288867, PubMed:26220143). Also regulates the levels of retinoic acid, a major metabolite of vitamin A involved in apoptosis, cellular growth and differentiation, and embryonic development (PubMed:10702251). Contributes to bile acid (BA) detoxification by catalyzing the glucuronidation of BA substrates, which are natural detergents for dietary lipids absorption (PubMed:23756265). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist losartan, caderastan and zolarsatan, drugs which can inhibit the effect of angiotensin II (PubMed:18674515). Also metabolizes mycophenolate, an immunosuppressive agent (PubMed:15470161)
- Specific Function
- glucuronosyltransferase activity
- Gene Name
- UGT2B7
- Uniprot ID
- P16662
- Uniprot Name
- UDP-glucuronosyltransferase 2B7
- Molecular Weight
- 60720.15 Da
References
- Precht JC, Schroth W, Klein K, Brauch H, Krynetskiy E, Schwab M, Murdter TE: The letrozole phase 1 metabolite carbinol as a novel probe drug for UGT2B7. Drug Metab Dispos. 2013 Nov;41(11):1906-13. doi: 10.1124/dmd.113.053405. Epub 2013 Aug 21. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
- Specific Function
- 1,8-cineole 2-exo-monooxygenase activity
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Jeong S, Woo MM, Flockhart DA, Desta Z: 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. doi: 10.1007/s00280-009-0935-7. Epub 2009 Feb 7. [Article]
- Bhatnagar AS: 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. [Article]
- FDA Approved Drug Products: Femara Letrozole Oral Tablets [Link]
- FDA Approved Drug Products: Kisquali Femara Co-Pack Letrozole and Ribociclib Succinate Oral Tablets [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase. Acts as a 1,4-cineole 2-exo-monooxygenase. Possesses low phenacetin O-deethylation activity
- Specific Function
- arachidonic acid epoxygenase activity
- Gene Name
- CYP2A6
- Uniprot ID
- P11509
- Uniprot Name
- Cytochrome P450 2A6
- Molecular Weight
- 56517.005 Da
References
- Jeong S, Woo MM, Flockhart DA, Desta Z: 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. doi: 10.1007/s00280-009-0935-7. Epub 2009 Feb 7. [Article]
- Raunio H, Rautio A, Gullsten H, Pelkonen O: Polymorphisms of CYP2A6 and its practical consequences. Br J Clin Pharmacol. 2001 Oct;52(4):357-63. [Article]
- Borrie AE, Rose RV, Choi YH, Perera FE, Read N, Sexton T, Lock M, Vandenberg TA, Hahn K, Dinniwell R, Younus J, Logan D, Potvin K, Yaremko B, Yu E, Lenehan J, Welch S, Tyndale RF, Teft WA, Kim RB: 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. doi: 10.1007/s10549-018-4910-z. Epub 2018 Aug 9. [Article]
- Bhatnagar AS: 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. [Article]
- FDA Approved Drug Products: Femara Letrozole Oral Tablets [Link]
- FDA Approved Drug Products: Kisquali Femara Co-Pack Letrozole and Ribociclib Succinate Oral Tablets [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- A cytochrome P450 monooxygenase that catalyzes the conversion of C19 androgens, androst-4-ene-3,17-dione (androstenedione) and testosterone to the C18 estrogens, estrone and estradiol, respectively (PubMed:27702664, PubMed:2848247). Catalyzes three successive oxidations of C19 androgens: two conventional oxidations at C19 yielding 19-hydroxy and 19-oxo/19-aldehyde derivatives, followed by a third oxidative aromatization step that involves C1-beta hydrogen abstraction combined with cleavage of the C10-C19 bond to yield a phenolic A ring and formic acid (PubMed:20385561). Alternatively, the third oxidative reaction yields a 19-norsteroid and formic acid. Converts dihydrotestosterone to delta1,10-dehydro 19-nordihydrotestosterone and may play a role in homeostasis of this potent androgen (PubMed:22773874). Also displays 2-hydroxylase activity toward estrone (PubMed:22773874). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:20385561, PubMed:22773874)
- Specific Function
- aromatase activity
- Gene Name
- CYP19A1
- Uniprot ID
- P11511
- Uniprot Name
- Aromatase
- Molecular Weight
- 57882.48 Da
References
- Azria D, Larbouret C, Cunat S, Ozsahin M, Gourgou S, Martineau P, Evans DB, Romieu G, Pujol P, Pelegrin A: Letrozole sensitizes breast cancer cells to ionizing radiation. Breast Cancer Res. 2005;7(1):R156-63. doi: 10.1186/bcr969. Epub 2004 Dec 7. [Article]
- Trosken ER, Fischer K, Volkel W, Lutz WK: Inhibition of human CYP19 by azoles used as antifungal agents and aromatase inhibitors, using a new LC-MS/MS method for the analysis of estradiol product formation. Toxicology. 2006 Feb 15;219(1-3):33-40. doi: 10.1016/j.tox.2005.10.020. Epub 2005 Dec 5. [Article]
- Dowsett M, Jones A, Johnston SR, Jacobs S, Trunet P, Smith IE: In vivo measurement of aromatase inhibition by letrozole (CGS 20267) in postmenopausal patients with breast cancer. Clin Cancer Res. 1995 Dec;1(12):1511-5. [Article]
- FDA Approved Drug Products: Femara Letrozole Oral Tablets [Link]
- FDA Approved Drug Products: Kisquali Femara Co-Pack Letrozole and Ribociclib Succinate Oral Tablets [Link]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Binder
- General Function
- Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
- Specific Function
- antioxidant activity
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Albumin
- Molecular Weight
- 69365.94 Da
References
- Bhatnagar AS: 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. [Article]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- ATP-dependent translocase ABCB1
- Molecular Weight
- 141477.255 Da
References
- Miyajima M, Kusuhara H, Takahashi K, Takashima T, Hosoya T, Watanabe Y, Sugiyama Y: Investigation of the effect of active efflux at the blood-brain barrier on the distribution of nonsteroidal aromatase inhibitors in the central nervous system. J Pharm Sci. 2013 Sep;102(9):3309-19. doi: 10.1002/jps.23600. Epub 2013 May 27. [Article]
Drug created at June 13, 2005 13:24 / Updated at October 21, 2024 08:50