There is a significant decrease in mean dermal thickness (P < 0.05) and changes in collagen bundles in the etretinate-treated mice group for a 28-day period compared to control groups. TUNEL assay shows that the density of TUNEL-positive cells in the dermis of etretinate-treated mice for a 14-day period is significantly increased (P < 0.05). The ratio of procollagen α 1 (I) chain to β actin mRNA from etretinate-treated mice for a 1-day period decreased significantly compared to that of the control mice, but the ratio from etretinatetreated mice for a 14-day period increased significantly (P < 0.05). Etretinate reduces dermal thickness, and suppresses the appearance of skin lesions by inducting apoptosis and perhaps regulation of cytokine expression in MRL/lpr mice.

Absorption, Distribution and Excretion
Absorption in the small intestine. Studies in healthy volunteers have shown that patients consuming whole milk or a high-fat diet have higher absorption rates of etretinate compared to fasting patients. After 1 to 36 months of treatment, the concentrations of etretinate and its active metabolites in epidermal samples depend on their distribution sites; subcutaneous tissue concentrations are significantly higher than serum concentrations, serum concentrations are higher than epidermal concentrations, and epidermal concentrations are higher than dermal concentrations. Eretinate accumulates at high concentrations in adipose tissue, particularly in the liver and subcutaneous fat. Patients receiving etretinate treatment for six months typically have higher liver concentrations than plasma concentrations, and these concentrations are often even higher in livers with high fatty infiltration. Studies in healthy volunteers have shown that patients consuming whole milk or a high-fat diet have higher absorption rates of etretinate compared to fasting patients. Eretinate is absorbed in the small intestine. For more complete data on the absorption, distribution, and excretion of etretinate (8 types), please visit the HSDB records page.

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Metabolism/Metabolites
Extensive metabolism, with significant first-pass metabolism, converting to a pharmacologically active acidic form. Subsequent metabolism produces an inactive 13-cis acid form, shortened chain breakdown products, and conjugates that are ultimately excreted.
Aromatic retinoic acid, tretinoin, is the major active metabolite of etretinate. This study investigated the ethyl esterification of tretinoin to etretinate using [(14)C] tretinoin and human liver microsomes. …This study shows that the ethyl esterification of tretinoin to etretinate in the presence of ethanol proceeds via the formation of tretinoin acyl-CoA. Predicting the clearance of tretinoin in vivo via this unique metabolic pathway will be challenging because the intracellular concentration of ethanol in humans can never be accurately predicted.

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Biological Half-Life
In one study, the apparent terminal half-life of etretinate after 6 months of treatment was approximately 120 days. In another study of 47 patients receiving long-term etretinate treatment, serum drug concentrations (0.5 to 12 ng/mL) were still detectable in 5 patients 2.1 to 2.9 years after the end of treatment. In one study, the apparent terminal half-life of etretinate after 6 months of treatment was approximately 120 days.

Protein Binding
Over 99% of etretinate is bound to plasma proteins, primarily lipoproteins, while its active metabolite, atratelate (etretinate), is primarily bound to albumin. Interactions
Eretinate used in combination with tetracyclines may increase the risk of pseudotumor cerebri. Eretinate used in combination with other photosensitizing drugs may produce additive photosensitizing effects. Eretinate used in combination with other hepatotoxic drugs (especially methotrexate) may increase the risk of hepatotoxicity. Eretinate used in combination with isotretinoin, retinoic acid, or vitamin A may produce additive toxic effects. For more complete data on drug interactions of etretinate (6 drugs in total), please visit the HSDB record page.

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Non-human toxicity
Mouse intraperitoneal LD50: 1176 mg/kg (20 days)
Rat intraperitoneal LD50: >2000 mg/kg (20 days)
Mouse oral LD50: >2000 mg/kg (20 days)
Rat oral LD50: >4000 mg/kg (20 days)

Clin Exp Dermatol.2009 Apr;34(3):385-9;Lupus.2005;14(7):510-6.

According to an independent committee of scientific and health experts, etratiate may cause developmental toxicity. Etratiate is a retinoid, belonging to the ester and ethyl ester class. It is a keratolytic agent. Etratiate is a drug used to treat severe psoriasis. It is a synthetic aromatic retinoid. The mechanism of action of etratiate is not fully understood, but similar to retinoic acid, it is thought to interfere with terminal differentiation of keratinocytes. It is believed to bind to retinoic acid receptors. Etratiate is also thought to enhance the binding of cAMP to the regulatory RI subunit of cAMP-dependent protein kinase. Due to the risk of birth defects, etratiate was withdrawn from the market in Canada and the United States in 1996 and 1998, respectively. Currently, etratiate is used to treat T-cell lymphoma. It also inhibits NADH oxidase activity. Etratiate is a synthetic oral retinoid and a prodrug of retinoic acid. Etratiate activates retinoic acid receptors, thereby inducing cell differentiation, inhibiting cell proliferation, and suppressing inflammatory cell infiltration into tissues. Due to its long half-life and potential teratogenic effects, etratiate has been discontinued in the United States. (NCI04)
An oral retinoid used to treat keratotic hereditary skin diseases, lichen planus, and psoriasis. It is also claimed to have benefits in preventing epithelial tumors. This compound may be teratogenic.

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Drug Indications
For the treatment of severe psoriasis in adults.

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Mechanism of Action
The mechanism of action of the active metabolite retinoic acid is not fully understood, but it is believed to help normalize the growth cycle of skin cells by targeting specific receptors (retinoid receptors) in the skin.

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Therapeutic Use
Anti-psoriasis drug
Etratiate is indicated for the treatment of severe, refractory psoriasis that is unresponsive to or intolerant to standard therapy, including erythrodermic and generalized pustular psoriasis. /Included on US Product Label/
Etratiate is used to treat severe, refractory oral lichen planus. /Not Included on Product Label/
Etratiate is also used to treat severe, refractory keratotic disorders such as: ichthyoid dermatitis; congenital ichthyosiform erythroderma; lamellar ichthyosis and other ichthyosis; keratosis pilaris (Daryl's disease); palmoplantar keratosis; pityriasis rubra pilaris (PRP); palmoplantar pustulosis. /Not Included on US Product Label/

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Drug Warnings
Pregnancy Risk Level: X /Contraindicated during pregnancy. Animal or human studies, as well as investigational or post-marketing reports, have demonstrated that the use of ettratiate may result in fetal malformations or risks that significantly outweigh any potential benefit to the patient. Etratiate is contraindicated during pregnancy because it can cause serious fetal malformations in humans, including myelomeningocele, meningocele, multiple suture closure, facial deformities, syndactyly, distal phalangeal agenesis, hip, ankle, and forearm deformities, cardiac and thymic abnormalities, low-set ears, high palate, decreased cranial volume, and skull and cervical spine changes. …The duration of pregnancy avoidance after discontinuation of the drug has not been established; follow-up of patients up to 2 years after discontinuation has shown that fetal malformations associated with etratiate also occurred during these 2 years. Therefore, women planning to conceive should not use etratiate. For women of childbearing potential, etratiate should not be used until the possibility of pregnancy has been ruled out. Furthermore, etratiate should not be used in women who are considered unreliable or unable to use reliable contraception during treatment and indefinitely after treatment. For more complete data on drug warnings (of 13) for etratiate, please visit the HSDB record page.

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Pharmacodynamics
The active metabolite responsible for the action of etratilate, retinoic acid, is a retinoid. Retinoids have a structure similar to vitamin A and participate in the normal growth of skin cells. Avitamin A acid works by inhibiting excessive cell proliferation and keratinization (the process by which skin cells thicken due to protein deposition), which are common in psoriasis. Therefore, it can reduce skin thickening, plaque formation, and scaling.

C23H30O3

354.48

354.219

54350-48-0

Etretinate-d3;1185237-13-1

5282375

Crystals

1.0±0.1 g/cm3

506.4±38.0 °C at 760 mmHg

104-105ºC

219.4±21.4 °C

0.0±1.3 mmHg at 25°C

1.544

6.77

0

3

8

26

568

0

O(C([H])([H])[H])C1C([H])=C(C([H])([H])[H])C(/C(/[H])=C(\[H])/C(=C(\[H])/C(/[H])=C(\[H])/C(=C(\[H])/C(=O)OC([H])([H])C([H])([H])[H])/C([H])([H])[H])/C([H])([H])[H])=C(C([H])([H])[H])C=1C([H])([H])[H]

HQMNCQVAMBCHCO-DJRRULDNSA-N

InChI=1S/C23H30O3/c1-8-26-23(24)14-17(3)11-9-10-16(2)12-13-21-18(4)15-22(25-7)20(6)19(21)5/h9-15H,8H2,1-7H3/b11-9+,13-12+,16-10+,17-14+

ethyl (2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.05 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)