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
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.
Concentrations of etretinate and its active metabolite in epidermal specimens obtained after 1 to 36 months of therapy were a function of location; subcutis much greater than serum greater than epidermis greater than dermis.
Etretinate accumulates in high concentrations in adipose tissue, especially in the liver and in subcutaneous fat. Liver concentrations of etretinate in patients who had received therapy for six months were generally higher than accompanying plasma concentrations and tended to be higher still in livers with a higher degree of fatty infiltration.
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.
Etretinate is absorbed in the small intestine.
For more Absorption, Distribution and Excretion (Complete) data for ETRETINATE (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
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.
The aromatic retinoid acitretin is the primary active metabolite of etretinate, and in this study the ethyl esterification of acitretin to etretinate using [(14)C]acitretin and human liver microsomes /was investigated/. ... This study demonstrated that in the presence of ethanol the ethyl esterification of acitretin to etretinate proceeds via formation of acitretinoyl-CoA. Predicting clearance of acitretin in vivo via this unique metabolic pathway will be a challenge, as the intracellular concentration of ethanol could never be predicted with any degree of accuracy in humans.

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Biological 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.
In one study, the apparent terminal half life of etretinate after 6 months of therapy was approximately 120 days.

Protein Binding
More than 99% bound to plasma proteins, predominantly lipoproteins, whereas its active metabolite, acetretin (etretin), is predominantly bound to albumin.

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Interactions
/Concurrent use of etretinate with tetracyclines/ may increase the potential for pseudotumor cerebri.
Concurrent use /with other photosensitizing medications/ may cause additive photosensitizing effects.
Concurrent use with other hepatotoxic medications, especially methotrexate, may increase the potential for hepatotoxicity.
/Concurrent use of etretinate with isotretinoin, tretinoin, or vitamin A/ may result in additive toxic effects.
For more Interactions (Complete) data for ETRETINATE (6 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Mouse ip 1176 mg/kg (20 days)
LD50 Rat ip >2000 mg/kg (20 days)
LD50 Mouse oral >2000 mg/kg (20 days)
LD50 Rat oral >4000 mg/kg (20 days)

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

Etretinate can cause developmental toxicity according to an independent committee of scientific and health experts.
Etretinate is a retinoid, an enoate ester and an ethyl ester. It has a role as a keratolytic drug.
Etretinate is a medication used to treat severe psoriasis. It is a synthetic aromatic retinoid. The mechanism of action of etretinate is still incompletely understood although, like retinoic acid, it is thought to interfere with the terminal differentiation of keratinocytes. It is thought to bind to the retinoic acid receptors. Etretinate is also believed to enhance the binding of cAMP to the regulatory RI subunit of cAMP dependent protein kinases. Etretinate was taken off the market in Canada in 1996 and America in 1998 due to the risk of birth defects. Etretinate is now used to treat T-cell lymphomas. It also appears to inhibit NADH oxidase activity.
Etretinate is a synthetic oral retinoid that is a prodrug of acitretin. Etretinate activates retinoid receptors, causing an induction of cell differentiation, inhibition of cell proliferation, and inhibition of tissue infiltration by inflammatory cells. Etretinate is no longer commercially available in the U.S. due to the extended potential for teratogenic effects related to its long half-life. (NCI04)
An oral retinoid used in the treatment of keratotic genodermatosis, lichen planus, and psoriasis. Beneficial effects have also been claimed in the prophylaxis of epithelial neoplasia. The compound may be teratogenic.

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Drug Indication
For the treatment of severe psoriasis in adults.

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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.

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Therapeutic Uses
Antipsoriatic
Etretinate is indicated for the treatment of severe recalcitrant psoriasis, including the erythrodermic and generalized pustular types, in patients who are unresponsive to or intolerant of the standard therapies. /Included in US product labeling/
Etretinate is used for the treatment of severe, intractable oral lichen planus. /NOT included in use product labeling/
Etretinate is also used in correcting severe intractable forms of keratinization disorders, such as: dermatoses, ichthyosiform; erythroderma, congenital ichthyosiform; ichthyosis, lamellar, and other ichthyoses; keratosis follicularis (Darier's disease); keratosis palmaris et plantaris; pityriasis rubra pilaris (PRP); pustulosis, palmoplanter. /NOT included in US product labeling/

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Drug Warnings
Pregnancy risk category: X /CONTRAINDICATED IN PREGNANCY. Studies in animals or humans, or investigational or post-marketing reports, have demonstrated positive evidence of fetal abnormalities or risk which clearly outweights any possible benefit to the patient./
Etretinate is contraindicated during pregnancy, since it has caused major human fetal abnormalities, including meningomyelocele; meningoencephalocoele; multiple synostoses; facial dysmorphia; syndactyly; absence of terminal phalanges; malformations of hip, ankle, and forearm; abnormalities of the heart and thymus; low set ears; high palate; decreased cranial volume; and alterations of the skull and cervical vertebrae.
... It has not been determined how long pregnancy should be avoided after discontinuation of treatment; patients have been followed for a long as 2 years after treatment was discontinued, and fetal abnormalities associated with etretinate have occurred during this 2 year period. Therefore, etretinate should not be used in women who plan to have children in the future.
In women of childbearing potential, etretinate should not be used until the possibility of pregnancy is ruled out. In addition, etretinate should not be used in women who, while undergoing treatment and for an indefinite period of time thereafter, are deemed unreliable in their use of contraception or who may not use reliable contraception.
For more Drug Warnings (Complete) data for ETRETINATE (13 total), please visit the HSDB record page.

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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.

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.)