Explore a selection of our essential drug information below, or:
Identification
- Summary
Estetrol is an estrogen used in combination with drospirenone for oral contraception.
- Brand Names
- Nextstellis 28 Day
- Generic Name
- Estetrol
- DrugBank Accession Number
- DB12235
- Background
Naturally or synthetically produced steroid estrogens have a wide range of pharmaceutical uses ranging from hormonal contraception to the treatment of menopausal symptoms.15 Estetrol (E4) is a native estrogen occurring naturally during pregnancy, but can be synthesized from a plant source and used for contraception.14 It is more potent and is safer than the synthetic estrogen ethinylestradiol (EE2) found in 97% of oral contraceptive pills, reducing the environmental accumulation of unwanted endocrine disrupting chemicals (EDCs) that often lead to harmful epigenetic effects.15
On April 15 2021, Mayne Pharma Group Limited and Mithra Pharmaceuticals were granted FDA approval for the oral contraceptive Estelle/Nextstellis, a combination of drospirenone and estetrol. Estetrol is the first new estrogen introduced to the USA in over 50 years and is the first approved estetrol product in the world. The combination of drospirenone and estetrol offers a new choice with a favourable safety profile for women seeking contraceptive therapy.14 In Canada, Nextstellis was approved for use in March 2021; it was developed by Mithra and is marketed by Searchlight Pharma.18
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Estetrol (DB12235)
- Weight
- Average: 304.3808
Monoisotopic: 304.167459256 - Chemical Formula
- C18H24O4
- Synonyms
- 15α-hydroxyestriol
- Estetrol
- Estétrol
- Estetrolum
- Oestetrol
Pharmacology
- Indication
Estetrol is indicated in combination with drospirenone for the prevention of pregnancy.13
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Therapies
- Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
- Mechanism of action
Estetrol is a synthetic analogue of a naturally occurring estrogen present during pregnancy, demonstrating selectivity for both estrogen receptor-α (ER-α) and ER-β and suppressing ovulation.13 Estetrol binds with a low to moderate affinity human estrogen receptor alpha (ER alpha) and ER beta with a preference for ER alpha.8 Estetrol demonstrates a unique mechanism of action via tissue selective activity, showing estrogen receptor agonist activity on the vagina, the uterus and the endometrium, and negative estrogenic activity on breast tissue.12,18
Target Actions Organism AEstrogen receptor agonistmodulatorregulatorHumans UEstrogen receptor beta agonistHumans - Absorption
Estetrol is rapidly absorbed from the gastrointestinal tract. The Cmax of estetrol is 18 ng/mL according to the results of a pharmacokinetic study, with an AUC of 36.4 ng•h/mL. When estetrol and drospirenone are taken in a single product, maximum serum concentrations of approximately 48.7 ng/mL are achieved within 1-3 h. Bioavailability of the combination ranges between 76 and 85%.17 The Tmax can range from 0.5 to 2 hours and time to steady state is approximately 4 days, according to the results of one clinical study.13
- Volume of distribution
Limited distribution of estetrol into red blood cells has been demonstrated.17
- Protein binding
Estetrol is 46-50% bound to plasma proteins.13 Estetrol does not bind to Sex Hormone Binding Globulin (SHBG). In one study, estetrol showed moderate binding to human plasma proteins (45.5%-50.4%) and human serum albumin (58.6%) with low binding to human alpha-glycoprotein (11.2%).17
- Metabolism
Estretol is heavily metabolized after oral administration.17 Phase 2 metabolism of estrogen forms glucuronide and sulfate conjugates with negligible in-vitro estrogenic activity. In vitro metabolism studies demonstrate that UGT2B7 catalyzes the formation of E4-16-glucuronide. Estetrol is combined with drospirenone in a product. The hepatic cytochrome enzyme CYP3A4 metabolizes drospirenone to two primary metabolites: the acid form of drospirenone through the opening of the lactone ring and the 4,5 dihydrodrospirenone formed by reduction, followed by sulfation. Both metabolites are pharmacologically inactive.13,17
- Route of elimination
Estrogens are generally excreted as sulfated and glucuronidated derivatives.11 Approximately 69% of a dose of estetrol is excreted in the urine, and about 22% is excreted in the feces as unchanged drug.13
- Half-life
The elimination half-life of estetrol is approximately 27 hours.13 Half-life may range between 19-40 hours.7
- Clearance
Not Available
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
LD50 information for estetrol is not readily available in the literature. Subjects receiving a dose of 20 mg, 40 mg or 60 mg of estetrol per day over 12 weeks were tolerated without dose-limiting toxicity.10 Symptoms that may occur in association with overdose, based on existing information on overdosage with oral contraceptives include nausea, vomiting, and vaginal bleeding. In one clinical study, 1 of 32 healthy research subjects receiving a dose of 75 mg of estretol with 15 mg of drospirenone for 10 days experienced deep vein thrombosis of the lower right limb. There is no known antidote to an estretol overdose; conduct laboratory testing for electrolytes and evidence of metabolic acidosis and provide symptomatic treatment.17
- 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 Estetrol can be increased when it is combined with Abametapir. Abatacept The metabolism of Estetrol can be increased when combined with Abatacept. Abciximab The risk or severity of adverse effects can be increased when Estetrol is combined with Abciximab. Abemaciclib The metabolism of Abemaciclib can be decreased when combined with Estetrol. Acalabrutinib The metabolism of Acalabrutinib can be decreased when combined with Estetrol. - Food Interactions
- Take with or without food. Take at the same time each day.
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 Ingredients
Ingredient UNII CAS InChI Key Estetrol monohydrate KC3GI9UM9V 2055649-81-3 XRJNAPXFAXBPAM-BVTDNVAGSA-N - International/Other Brands
- Donesta
- Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Drovelis Estetrol monohydrate (14.2 mg) + Drospirenone (3 mg) Tablet, film coated Oral Gedeon Richter Plc 2021-10-12 Not applicable EU 
Drovelis Estetrol monohydrate (14.2 mg) + Drospirenone (3 mg) Tablet, film coated Oral Gedeon Richter Plc 2021-10-12 Not applicable EU Drovelis Estetrol monohydrate (14.2 mg) + Drospirenone (3 mg) Tablet, film coated Oral Gedeon Richter Plc 2021-10-12 Not applicable EU Drovelis Estetrol monohydrate (14.2 mg) + Drospirenone (3 mg) Tablet, film coated Oral Gedeon Richter Plc 2021-10-12 Not applicable EU Lydisilka Estetrol monohydrate (14.2 mg) + Drospirenone (3 mg) Tablet, film coated Oral Estetra Srl 2021-10-15 Not applicable EU
Categories
- ATC Codes
- G03AA18 — Drospirenone and estetrol
- Drug Categories
- Adrenal Cortex Hormones
- Contraceptives, Oral
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates (strength unknown)
- Cytochrome P-450 Substrates
- Estradiol Congeners
- Estranes
- Estrenes
- Estrogen Contraceptives
- Estrogens
- Estrogens, agonists
- Fused-Ring Compounds
- Genito Urinary System and Sex Hormones
- Gonadal Hormones
- Gonadal Steroid Hormones
- Hormonal Contraceptives for Systemic Use
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Sex Hormones and Modulators of the Genital System
- Steroids
- UGT2B7 substrates
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as estrogens and derivatives. These are steroids with a structure containing a 3-hydroxylated estrane.
- Kingdom
- Organic compounds
- Super Class
- Lipids and lipid-like molecules
- Class
- Steroids and steroid derivatives
- Sub Class
- Estrane steroids
- Direct Parent
- Estrogens and derivatives
- Alternative Parents
- 3-hydroxysteroids / 17-hydroxysteroids / 16-alpha-hydroxysteroids / Phenanthrenes and derivatives / Tetralins / 1-hydroxy-2-unsubstituted benzenoids / Secondary alcohols / Cyclic alcohols and derivatives / Polyols / Hydrocarbon derivatives
- Substituents
- 1-hydroxy-2-unsubstituted benzenoid / 15-hydroxysteroid / 16-alpha-hydroxysteroid / 16-hydroxysteroid / 17-hydroxysteroid / 3-hydroxysteroid / Alcohol / Aromatic homopolycyclic compound / Benzenoid / Cyclic alcohol
- Molecular Framework
- Aromatic homopolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- ENB39R14VF
- CAS number
- 15183-37-6
- InChI Key
- AJIPIJNNOJSSQC-NYLIRDPKSA-N
- InChI
- InChI=1S/C18H24O4/c1-18-7-6-12-11-5-3-10(19)8-9(11)2-4-13(12)14(18)15(20)16(21)17(18)22/h3,5,8,12-17,19-22H,2,4,6-7H2,1H3/t12-,13-,14-,15-,16-,17+,18+/m1/s1
- IUPAC Name
- (1R,2R,3R,3aS,3bR,9bS,11aS)-11a-methyl-1H,2H,3H,3aH,3bH,4H,5H,9bH,10H,11H,11aH-cyclopenta[a]phenanthrene-1,2,3,7-tetrol
- SMILES
- [H][C@@]12[C@@H](O)[C@@H](O)[C@H](O)[C@@]1(C)CC[C@]1([H])C3=CC=C(O)C=C3CC[C@@]21[H]
References
- Synthesis Reference
Johannes Jan Platteeuw, Herman Jan Tijmen, Coelingh Bennink, Franciscus Wilhelmus, Petrus Damen, Michiel Christian, Alexander Van Vliet. (2013).Process for the preparation of estetrol. (WO2013012328A1).https://patents.google.com/patent/WO2013012328A1/en18
- General References
- Apter D, Zimmerman Y, Beekman L, Mawet M, Maillard C, Foidart JM, Coelingh Bennink HJT: Estetrol combined with drospirenone: an oral contraceptive with high acceptability, user satisfaction, well-being and favourable body weight control. Eur J Contracept Reprod Health Care. 2017 Aug;22(4):260-267. doi: 10.1080/13625187.2017.1336532. Epub 2017 Jun 22. [Article]
- Montt-Guevara MM, Giretti MS, Russo E, Giannini A, Mannella P, Genazzani AR, Genazzani AD, Simoncini T: Estetrol Modulates Endothelial Nitric Oxide Synthesis in Human Endothelial Cells. Front Endocrinol (Lausanne). 2015 Jul 22;6:111. doi: 10.3389/fendo.2015.00111. eCollection 2015. [Article]
- Gaspard U, Taziaux M, Mawet M, Jost M, Gordenne V, Coelingh Bennink HJT, Lobo RA, Utian WH, Foidart JM: A multicenter, randomized study to select the minimum effective dose of estetrol (E4) in postmenopausal women (E4Relief): part 1. Vasomotor symptoms and overall safety. Menopause. 2020 Aug;27(8):848-857. doi: 10.1097/GME.0000000000001561. [Article]
- Abot A, Fontaine C, Buscato M, Solinhac R, Flouriot G, Fabre A, Drougard A, Rajan S, Laine M, Milon A, Muller I, Henrion D, Adlanmerini M, Valera MC, Gompel A, Gerard C, Pequeux C, Mestdagt M, Raymond-Letron I, Knauf C, Ferriere F, Valet P, Gourdy P, Katzenellenbogen BS, Katzenellenbogen JA, Lenfant F, Greene GL, Foidart JM, Arnal JF: The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor alpha modulation, uncoupling nuclear and membrane activation. EMBO Mol Med. 2014 Oct;6(10):1328-46. doi: 10.15252/emmm.201404112. [Article]
- Grandi G, Del Savio MC, Lopes da Silva-Filho A, Facchinetti F: Estetrol (E4): the new estrogenic component of combined oral contraceptives. Expert Rev Clin Pharmacol. 2020 Apr;13(4):327-330. doi: 10.1080/17512433.2020.1750365. Epub 2020 Apr 7. [Article]
- Coelingh Bennink HJT, Verhoeven C, Zimmerman Y, Visser M, Foidart JM, Gemzell-Danielsson K: Pharmacokinetics of the fetal estrogen estetrol in a multiple-rising-dose study in postmenopausal women. Climacteric. 2017 Jun;20(3):285-289. doi: 10.1080/13697137.2017.1291608. Epub 2017 Mar 7. [Article]
- Visser M, Holinka CF, Coelingh Bennink HJ: First human exposure to exogenous single-dose oral estetrol in early postmenopausal women. Climacteric. 2008;11 Suppl 1:31-40. doi: 10.1080/13697130802056511. [Article]
- Visser M, Foidart JM, Coelingh Bennink HJ: In vitro effects of estetrol on receptor binding, drug targets and human liver cell metabolism. Climacteric. 2008;11 Suppl 1:64-8. doi: 10.1080/13697130802050340. [Article]
- Duijkers IJ, Klipping C, Zimmerman Y, Appels N, Jost M, Maillard C, Mawet M, Foidart JM, Coelingh Bennink HJ: Inhibition of ovulation by administration of estetrol in combination with drospirenone or levonorgestrel: Results of a phase II dose-finding pilot study. Eur J Contracept Reprod Health Care. 2015;20(6):476-89. doi: 10.3109/13625187.2015.1074675. [Article]
- Schmidt M, Lenhard H, Hoenig A, Zimmerman Y, Krijgh J, Jansen M, Coelingh Bennink HJT: Tumor suppression, dose-limiting toxicity and wellbeing with the fetal estrogen estetrol in patients with advanced breast cancer. J Cancer Res Clin Oncol. 2020 Nov 26. pii: 10.1007/s00432-020-03472-8. doi: 10.1007/s00432-020-03472-8. [Article]
- Thomas MP, Potter BV: The structural biology of oestrogen metabolism. J Steroid Biochem Mol Biol. 2013 Sep;137:27-49. doi: 10.1016/j.jsbmb.2012.12.014. Epub 2013 Jan 4. [Article]
- Singer CF, Bennink HJ, Natter C, Steurer S, Rudas M, Moinfar F, Appels N, Visser M, Kubista E: Antiestrogenic effects of the fetal estrogen estetrol in women with estrogen-receptor positive early breast cancer. Carcinogenesis. 2014 Nov;35(11):2447-51. doi: 10.1093/carcin/bgu144. Epub 2014 Jul 5. [Article]
- FDA Approved Drug Products: NEXTSTELLIS (drospirenone and estetrol) tablets for oral use [Link]
- Joint press release, Mayne Pharma and Mithra: MAYNE PHARMA AND MITHRA ANNOUNCE FDA APPROVAL OF NEW ORAL CONTRACEPTIVE NEXTSTELLIS [Link]
- Mithra Women's Health: E4 Paves the Road Towards a Revolutionary Era of Environmental Friendly Medicines [Link]
- Cayman Chem MSDS: Estetrol hydrate [Link]
- Product monograph: Nexstellis (estetrol and drospirenone) oral tablets [Link]
- Newswire: Mithra and Searchlight Pharma Announce Nextstellis® Approval in Canada [Link]
- External Links
- PubChem Compound
- 27125
- PubChem Substance
- 347828514
- ChemSpider
- 25245
- BindingDB
- 158505
- 2539031
- ChEBI
- 142773
- ChEMBL
- CHEMBL1230314
- ZINC
- ZINC000005764481
- PDBe Ligand
- 4OH
- Wikipedia
- Estetrol
- PDB Entries
- 3l03
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 Recruiting Treatment Cervical Mucus / Serum Hormonal Profile / Ultrasound Finding: Ovulation Inhibition, Ovarian Activities 1 somestatus stop reason just information to hide 4 Completed Treatment Endometrial Diseases / Endometrial Polyps 2 somestatus stop reason just information to hide 4 Not Yet Recruiting Treatment Coronavirus Disease 2019 (COVID‑19) / Endometriotic Cysts / Ovarian Endometrioma 1 somestatus stop reason just information to hide 3 Active Not Recruiting Treatment Menopausal Symptoms / Vasomotor Symptoms Associated With Menopause 1 somestatus stop reason just information to hide 3 Completed Prevention Contraception 2 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral Kit; tablet, film coated Oral Tablet Oral - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US7732430 No 2010-06-08 2025-03-02 US 
US11793760 No 2016-06-17 2036-06-17 US US11957694 No 2016-06-17 2036-06-17 US US11964055 No 2016-06-17 2036-06-17 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 233-236 https://www.chemicalbook.com/ChemicalProductProperty_EN_CB1210710.htm boiling point (°C) 491.9±45.0 https://www.chemicalbook.com/ChemicalProductProperty_EN_CB1210710.htm logP 2.62 https://www.embopress.org/doi/full/10.15252/emmm.201404112 pKa 10.22±0.70 https://www.chemicalbook.com/ChemicalProductProperty_EN_CB1210710.htm - Predicted Properties
Property Value Source logP 1.67 Chemaxon pKa (Strongest Acidic) 10.33 Chemaxon pKa (Strongest Basic) -3.3 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 4 Chemaxon Polar Surface Area 80.92 Å2 Chemaxon Rotatable Bond Count 0 Chemaxon Refractivity 82.55 m3·mol-1 Chemaxon Polarizability 33.88 Å3 Chemaxon Number of Rings 4 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
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0a4i-0019000000-fe3bcdfefc512b4df7ba Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0udi-0029000000-468fff7d894551f008a7 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-052s-0592000000-d434c30044141d847217 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0udr-0098000000-66fe9952e6d39852d6eb Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0h4y-0091000000-791caf6842e6a72deb06 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0301-0930000000-fb4ddc6a8504b8f35199 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 181.6395217 predictedDarkChem Lite v0.1.0 [M-H]- 167.66869 predictedDeepCCS 1.0 (2019) [M+H]+ 186.2964217 predictedDarkChem Lite v0.1.0 [M+H]+ 169.66463 predictedDeepCCS 1.0 (2019) [M+Na]+ 187.1327217 predictedDarkChem Lite v0.1.0 [M+Na]+ 175.57715 predictedDeepCCS 1.0 (2019)
Targets
Build, predict & validate machine-learning models
Use our structured and evidence-based datasets to unlock newinsights and accelerate drug research.
Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- AgonistModulatorRegulator
- General Function
- Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3 (PubMed:17922032). Maintains neuronal survival in response to ischemic reperfusion injury when in the presence of circulating estradiol (17-beta-estradiol/E2) (By similarity)
- Specific Function
- 14-3-3 protein binding
- Gene Name
- ESR1
- Uniprot ID
- P03372
- Uniprot Name
- Estrogen receptor
- Molecular Weight
- 66215.45 Da
References
- Gaspard U, Taziaux M, Mawet M, Jost M, Gordenne V, Coelingh Bennink HJT, Lobo RA, Utian WH, Foidart JM: A multicenter, randomized study to select the minimum effective dose of estetrol (E4) in postmenopausal women (E4Relief): part 1. Vasomotor symptoms and overall safety. Menopause. 2020 Aug;27(8):848-857. doi: 10.1097/GME.0000000000001561. [Article]
- Abot A, Fontaine C, Buscato M, Solinhac R, Flouriot G, Fabre A, Drougard A, Rajan S, Laine M, Milon A, Muller I, Henrion D, Adlanmerini M, Valera MC, Gompel A, Gerard C, Pequeux C, Mestdagt M, Raymond-Letron I, Knauf C, Ferriere F, Valet P, Gourdy P, Katzenellenbogen BS, Katzenellenbogen JA, Lenfant F, Greene GL, Foidart JM, Arnal JF: The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor alpha modulation, uncoupling nuclear and membrane activation. EMBO Mol Med. 2014 Oct;6(10):1328-46. doi: 10.15252/emmm.201404112. [Article]
- Benoit T, Valera MC, Fontaine C, Buscato M, Lenfant F, Raymond-Letron I, Tremollieres F, Soulie M, Foidart JM, Game X, Arnal JF: Estetrol, a Fetal Selective Estrogen Receptor Modulator, Acts on the Vagina of Mice through Nuclear Estrogen Receptor alpha Activation. Am J Pathol. 2017 Nov;187(11):2499-2507. doi: 10.1016/j.ajpath.2017.07.013. Epub 2017 Aug 19. [Article]
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Agonist
- General Function
- Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1/ER-alpha, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner (PubMed:20074560)
- Specific Function
- DNA binding
- Gene Name
- ESR2
- Uniprot ID
- Q92731
- Uniprot Name
- Estrogen receptor beta
- Molecular Weight
- 59215.765 Da
References
- Montt-Guevara MM, Giretti MS, Russo E, Giannini A, Mannella P, Genazzani AR, Genazzani AD, Simoncini T: Estetrol Modulates Endothelial Nitric Oxide Synthesis in Human Endothelial Cells. Front Endocrinol (Lausanne). 2015 Jul 22;6:111. doi: 10.3389/fendo.2015.00111. eCollection 2015. [Article]
Enzymes
- 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
- 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
- Gall WE, Zawada G, Mojarrabi B, Tephly TR, Green MD, Coffman BL, Mackenzie PI, Radominska-Pandya A: Differential glucuronidation of bile acids, androgens and estrogens by human UGT1A3 and 2B7. J Steroid Biochem Mol Biol. 1999 Jul-Aug;70(1-3):101-8. doi: 10.1016/s0960-0760(99)00088-6. [Article]
- FDA Approved Drug Products: NEXTSTELLIS (drospirenone and estetrol) tablets for oral use [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
- FDA Approved Drug Products: NEXTSTELLIS (drospirenone and estetrol) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Binder
- General Function
- Functions as a transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in the body. Appears to function in modulating the activity of the immune system during the acute-phase reaction
- Specific Function
- Not Available
- Gene Name
- ORM1
- Uniprot ID
- P02763
- Uniprot Name
- Alpha-1-acid glycoprotein 1
- Molecular Weight
- 23539.43 Da
References
- Product monograph: Nexstellis (estetrol and drospirenone) oral tablets [Link]
Drug created at October 20, 2016 21:41 / Updated at August 26, 2024 19:23