エトレチナート

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

104-105

104-105 °C

Danger

H315 (100%): Causes skin irritation [Warning Skin corrosion/irritation]

P203, P261, P264, P264+P265, P271, P273, P280, P302+P352, P304+P340, P305+P351+P338, P318, P319, P321, P332+P317, P337+P317, P362+P364, P391, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 5 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

/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.

/HUMAN EXPOSURE STUDIES/ 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.

/HUMAN EXPOSURE STUDIES/ ...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.

/CASE REPORTS/ Three patients who received etretinate, two for psoriasis vulgaris and one for exfoliative dermatitis, developed clinical and electromyographic features of muscle damage during treatment. In one patient histological and ultrastructural findings indicated segmental muscle necrosis. Withdrawal of the drug led to clinical recovery and normalization of muscle enzyme levels and electromyogram.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

ETRETINATE

DILI Positive

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In an 80 week study, the high dose male group, but not the high dose female group, of Crl:CD-1 (ICR) BR mice given doses of 4 to 5 mg/kg per day of etretinate had an increase incidence of blood vessel tumors.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ When female SD rats were continuously treated with etretinate throughout pre-mating, gestation, and lactation periods, the resulting F1 pups exhibited low viability and inhibition of somatic growth after birth. Nevertheless, these pups showed no notable change in body weight and external appearance at birth. The cross-fostering (between control and treated groups) method /was used/ and the neonatal viability and the growth hormonal changes /was investigated/ in order to assess which treatment period of gestation or lactation was mainly involved in these effects and what changes were actually induced in the F1 pups. The results showed that low viability and inhibition of somatic growth after birth were mainly related to treatment during the gestation period, and these effects were augmented by treatment during the lactation period. Serum GH and IGF-I levels were increased on day 21 in F1 pups groups in which inhibition of somatic growth was observed. These results indicated that treatment with etretinate during the gestation period might induce a decrease in the number of receptors of GH and IGF-I or other changes, such as a poor-response in target tissues due to a down-regulation, with an increase of serum GH and IGF-I levels.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ ... the experimental induction of anorectal malformations (ARM) and other internal and external malformations in mouse fetuses induced by maternal administration of etretinate, a long-acting vitamin A analogue /is reported/. The teratogen was administered to pregnant mice between the 7th and 10th gestational days (E7 and E10). The mice of the control group were given pure sesame oil on E9. /The authors/ examined survival rates, crown-rump length, and the incidence of internal and external malformations, with particular attention to ARM, in each group. All mice in the E8 group exhibited rectovesical fistula, hydronephrosis, and spina bifida. All males and females in the E9 group given 60 mg/kg of etretinate developed rectoprostatic urethral fistula and rectocloacal fistula, respectively. The E10 group, given 60 mg/kg of etretinate displayed cleft palate (63.6%), forelimb malformation (68.2%), and a short club-shaped tail (100%). The fetuses had more severe types of ARM when etretinate had been administered on an earlier gestational day. The E9 group is a useful model for anorectal malformation, whereas the E8 group is a model for hydronephrosis and spina bifida.

/GENOTOXICITY/ Except for a weakly positive response in the Ames test when the tester strain TA100 was used, there was no evidence of genotoxicity when etretinate was evaluated by the Ames test in a host-mediated assay, in the micronucleus test, and in a "treat and 'late" test using the diploid yeast strain S. cerevisiae D7. In addition, no differences were noted in the rate of sister chromatid

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)

D - Dermatologicals

QD - Dermatologicals

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.

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.

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.

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.

MEDICATION: Antipsoriatic

Discontinued drug.