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Etretinate | CAS No: 54350-48-0 | GMP-certified suppliers
A medication that treats severe adult psoriasis by modulating skin cell proliferation and differentiation, requiring stringent quality control due to teratogenic risks and chemical stability concerns.
Therapeutic categories
Primary indications
- For the treatment of severe psoriasis in adults
Product Snapshot
- Etretinate is an oral small molecule formulated as capsules
- It is primarily indicated for the treatment of severe psoriasis in adults
- The product has been withdrawn from regulatory markets and is no longer approved for use
Clinical Overview
Pharmacodynamically, etretinate is a prodrug whose biological activity is largely attributed to its active metabolite, acitretin. Retinoids, structurally related to vitamin A, regulate skin cell proliferation and differentiation. Acitretin moderates the hyperproliferation and abnormal keratinization characteristic of psoriatic lesions, reducing epidermal thickening, plaque formation, and scaling.
The precise mechanism of action remains incompletely elucidated. Etretinate and its metabolite are believed to bind retinoid receptors (RARs and RXRs), nuclear receptors that modulate gene expression involved in keratinocyte terminal differentiation and proliferation. Additionally, etretinate may enhance the binding of cyclic AMP to the regulatory RI subunit of cAMP-dependent protein kinases and inhibit NADH oxidase activity, but the clinical relevance of these actions is not well established.
Key absorption, distribution, metabolism, and excretion (ADME) characteristics include a prolonged half-life of etretinate due to extensive tissue accumulation, especially in adipose tissue, which contributes to sustained systemic exposure and complicates treatment discontinuation. Biotransformation yields acitretin as an active metabolite with a shorter half-life. Elimination occurs primarily via hepatic metabolism and biliary excretion.
Safety and toxicity considerations center on etretinate’s pronounced teratogenic potential, mandating strict contraceptive measures during and for an extended period after treatment. Other adverse effects include mucocutaneous symptoms, hepatotoxicity, and possible photosensitization.
Currently, etretinate is no longer widely used for psoriasis management and has limited application in T-cell lymphomas. Retinoids with improved safety profiles have largely replaced its use.
From an API sourcing perspective, etretinate requires rigorous quality control due to its chemical stability issues and strict regulatory controls associated with teratogenic risk. Suppliers must provide comprehensive documentation on purity, impurity profiles, residual solvents, and compliance with controlled substance regulations. Stability data and validated storage conditions are critical given the compound’s lipophilicity and long tissue half-life.
Identification & chemistry
| Generic name | Etretinate |
|---|---|
| Molecule type | Small molecule |
| CAS | 54350-48-0 |
| UNII | 65M2UDR9AG |
| DrugBank ID | DB00926 |
Pharmacology
| Summary | Acitretin, the active metabolite of etretinate, is a retinoid that modulates retinoic acid receptors (RARs and RXRs) to regulate the differentiation and proliferation of skin cells. It normalizes keratinocyte growth and reduces hyperkeratosis, plaque formation, and scaling associated with severe psoriasis. Its pharmacodynamic effects focus on correcting abnormal skin cell turnover characteristic of the disease. |
|---|---|
| Mechanism of action | The mechanism of action of the active metabolite, acitretin, is unknown, however it is believed to work by targeting specific receptors (retinoid receptors) in the skin which help normalize the growth cycle of skin cells. |
| Pharmacodynamics | The active metabolite responsible for etretinate's effects, acitretin, is a retinoid. Retinoids have a structure similar to vitamin A and are involved in the normal growth of skin cells. Acitretin works by inhibiting the excessive cell growth and keratinisation (process by which skin cells become thickened due to the deposition of a protein within them) seen in psoriasis. It therefore reduces the thickening of the skin, plaque formation and scaling. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Retinoic acid receptor alpha | Humans | agonist |
| Retinoic acid receptor RXR-alpha | Humans | agonist |
| Retinoic acid receptor beta | Humans | agonist |
ADME / PK
| Absorption | Absorbed in the small intestine. Studies in normal volunteers indicate that the absorption of etretinate is greater in patients consuming whole milk or a high-fat diet than in patients in a fasting state. |
|---|---|
| Half-life | In one study, the apparent terminal half-life of etretinate after 6 months of therapy was approximately 120 days. In another study of 47 patients who had undergone chronic therapy with etretinate, 5 patients had detectable serum drug concentrations (0.5 to 12 ng/mL) 2.1 to 2.9 years after therapy was completed. |
| Protein binding | More than 99% bound to plasma proteins, predominantly lipoproteins, whereas its active metabolite, acetretin (etretin), is predominantly bound to albumin. |
| Metabolism | Extensively metabolized, with significant first-pass metabolism to the pharmacologically active acid form. Subsequent metabolism results in the inactive 13-cis acid form, chain-shortened breakdown products, and conjugates that are ultimately excreted. |
Formulation & handling
- Etretinate is a lipophilic small molecule retinoid ester formulated for oral administration, typically in capsule form.
- The compound exhibits very low aqueous solubility, requiring careful consideration of formulation strategies to enhance bioavailability.
- Patient handling must emphasize strict avoidance of alcohol during treatment and for up to two months post-discontinuation due to significant interaction risks.
Regulatory status
Supply Chain
| Supply chain summary | Etretinate is manufactured by a single originator company, Hoffmann-La Roche Inc. Its branded products have a presence primarily in the US and European markets. Given the limited number of manufacturers and the fact that etretinate is an older compound, patent expiry has likely led to existing generic competition. |
|---|
Safety
| Toxicity | Symptoms of overdose include headache and vertigo. |
|---|
- Exposure may cause central nervous system effects such as headache and vertigo
- Handle with appropriate personal protective equipment to avoid inhalation or skin contact
- Use in well-ventilated areas to minimize occupational exposure
Etretinate is a type of Retinoids
Retinoids are a subcategory of pharmaceutical active pharmaceutical ingredients (APIs) widely used in dermatology and skincare products. Derived from vitamin A, retinoids play a crucial role in promoting skin health and treating various skin conditions. They are popular due to their proven effectiveness in combating acne, reducing wrinkles, and improving overall skin texture.
Retinoids work by binding to specific receptors in the skin cells, influencing gene expression and cellular processes. This action helps regulate the growth and differentiation of skin cells, promoting the turnover of old cells and the production of new, healthier cells. As a result, retinoids can unclog pores, reduce sebum production, and prevent the formation of acne lesions.
Furthermore, retinoids stimulate collagen production, which enhances skin elasticity and reduces the appearance of fine lines and wrinkles. They also possess antioxidant properties, protecting the skin from damage caused by environmental factors such as UV radiation.
Common retinoids used in skincare formulations include retinol, retinaldehyde, and tretinoin (also known as all-trans retinoic acid). These compounds vary in their potency and stability, with tretinoin being the most potent and retinol requiring conversion within the skin to become active.
However, it is important to note that retinoids may cause skin irritation, redness, and dryness, especially during the initial stages of usage. Gradual introduction and proper skincare routines can help minimize these side effects.
In summary, retinoids are a highly sought-after subcategory of pharmaceutical APIs for their significant benefits in skincare. They offer a promising solution for those seeking to improve their skin's health, combat acne, and reduce signs of aging.
Etretinate (Retinoids), classified under Dermatological Agents
Dermatological agents are a vital category of pharmaceutical active pharmaceutical ingredients (APIs) used in the formulation of various skincare and dermatology products. These APIs are specifically designed to target and treat skin conditions, offering effective solutions for a wide range of dermatological concerns.
Dermatological agents encompass a diverse array of compounds, including corticosteroids, antifungal agents, antibacterials, retinoids, and immunomodulators. Each API within this category possesses unique properties and mechanisms of action, enabling them to address specific skin-related issues.
Corticosteroids, for instance, are potent anti-inflammatory agents commonly used in the treatment of skin conditions like eczema, psoriasis, and dermatitis. Antifungal agents, on the other hand, combat fungal infections such as athlete's foot or ringworm. Antibacterials are effective against bacterial infections, while retinoids promote skin cell turnover and treat acne and photoaging. Immunomodulators regulate the immune response, providing relief from conditions like atopic dermatitis.
The development and application of dermatological APIs involve rigorous research, clinical trials, and regulatory compliance. These APIs are typically integrated into topical creams, ointments, gels, and lotions, ensuring targeted delivery to the affected areas of the skin.
Dermatological agents play a crucial role in the management and treatment of various skin disorders. By harnessing the therapeutic properties of these APIs, pharmaceutical companies can develop innovative skincare products that cater to the diverse needs of individuals seeking effective dermatological solutions.
