体外活性：Etretinate（Ro 10-9359）是第二代类维生素A，用于治疗严重银屑病；已被阿维A取代，阿维A是阿维A酯的更安全的代谢物。细胞测定：将HSC-5细胞以1.5×103/100μL的密度接种于96孔板中并用于实验。进行初步实验以确定阿维A酯的有效剂量和细胞毒性。将细胞与浓度为 5、10、25 和 50 nmol/L 的阿维A酯一起孵育 72 小时 [溶解在含有 0.0001% 二甲基亚砜 (DMSO) 的盐水中]。然后将细胞在有或没有 200 μmol/L ALA (Sigma) 的情况下再孵育 2 小时。然后使用金属卤化物灯以 10、20、40 和 80 J/cm2 的剂量照射每个板。

与对照组相比，28 天的阿维A酯治疗组小鼠的平均真皮厚度显着降低（P < 0.05），胶原束也发生变化。 TUNEL检测显示，阿维A酯治疗小鼠真皮中TUNEL阳性细胞密度14天显着增加（P < 0.05）。与对照小鼠相比，阿维A酯治疗1天的小鼠的前胶原α1（I）链与β肌动蛋白mRNA的比率显着下降，但阿维A酯治疗14天的小鼠的比率显着增加（ P<0.05）。 Etretinate 通过诱导细胞凋亡并可能调节 MRL/lpr 小鼠的细胞因子表达来减少真皮厚度并抑制皮肤病变的出现。

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

35.53

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (7.05 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL 澄清 DMSO 储备液加入900 μL 玉米油中，混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。