Estetrol API Manufacturers

General Description:

Estetrol, identified by CAS number 15183-37-6, is a notable compound with significant therapeutic applications. Naturally or synthetically produced steroid estrogens have a wide range of pharmaceutical uses ranging from hormonal contraception to the treatment of menopausal symptoms. Estetrol (E4) is a native estrogen occurring naturally during pregnancy, but can be synthesized from a plant source and used for contraception. 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. On April 15 2021, Mayne Pharma Group Limited and Mithra Pharmaceuticals were granted FDA approval for the oral contraceptive Estelle/Nextstellis, a combination of 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. In Canada, Nextstellis was approved for use in March 2021; it was developed by Mithra and is marketed by Searchlight Pharma.

Indications:

This drug is primarily indicated for: Estetrol is indicated in combination with drospirenone for the prevention of pregnancy. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Estetrol undergoes metabolic processing primarily in: Estretol is heavily metabolized after oral administration. 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 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. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Estetrol are crucial for its therapeutic efficacy: 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%. 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. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Estetrol is an important consideration for its dosing schedule: The elimination half-life of estetrol is approximately 27 hours. Half-life may range between 19-40 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Estetrol exhibits a strong affinity for binding with plasma proteins: Estetrol is 46-50% bound to plasma proteins. 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%). This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Estetrol from the body primarily occurs through: Estrogens are generally excreted as sulfated and glucuronidated derivatives. Approximately 69% of a dose of estetrol is excreted in the urine, and about 22% is excreted in the feces as unchanged drug. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Estetrol is distributed throughout the body with a volume of distribution of: Limited distribution of estetrol into red blood cells has been demonstrated. This metric indicates how extensively the drug permeates into body tissues.

Pharmacodynamics:

Estetrol exerts its therapeutic effects through: Estetrol prevents pregnancy by suppressing ovulation. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Estetrol functions by: 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. Estetrol binds with a low to moderate affinity human estrogen receptor alpha (ER alpha) and ER beta with a preference for ER alpha. 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. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Estetrol belongs to the class of organic compounds known as estrogens and derivatives. These are steroids with a structure containing a 3-hydroxylated estrane, classified under the direct parent group Estrogens and derivatives. This compound is a part of the Organic compounds, falling under the Lipids and lipid-like molecules superclass, and categorized within the Steroids and steroid derivatives class, specifically within the Estrane steroids subclass.

Categories:

Estetrol is categorized under the following therapeutic classes: 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. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Estetrol include:

• Melting Point: 233-236
• Boiling Point: 491.9±45.0
• logP: 2.62
• pKa: 10.22±0.70