In mice used as models for Alzheimer's disease, citiretin (10 mg/kg; intraperitoneal; ip for 7 days) raises IL-6 in the central nervous system[3].

Absorption, Distribution and Excretion
Oral absorption of acitretin is optimal when given with food, and is linear and proportional with increasing doses from 25 to 100 mg. Approximately 72% (range 47% to 109%) of the administered dose was absorbed after a single 50 mg dose of acitretin was given to 12 healthy subjects.
Both parent compound and isomer are further metabolized into chain-shortened breakdown products and conjugates, which are excreted. The chain-shortened metabolites and conjugates of acitretin and cis-acitretin are ultimately excreted in the feces (34% to 54%) and urine (16% to 53%).
/MILK/ Acitretin is distributed into milk ... .
/MILK/ Retinoid transfer into breast milk was studied in a psoriatric woman receiving oral acitretin at a dosage of 40 mg once daily. Concentrations of the parent compound and its main metabolite, 13-cis acitretin, were measured in serum and mature milk during the initial nine days of therapy, using reverse-phase high performance liquid chromatography. At steady-state, trace amounts of the drug and metabolite (30-40 ng/mL) appeared in breast milk corresponding to a milk/serum concentration ratio of about 0.18. Acitretin was almost exclusively distributed in the fatty layers of the milk. Although the estimated amount of the drug consumed by a suckling infant would correspond to only 1.5% of the maternal dose, the toxic potential of acitretin justifies its avoidance in breast-feeding women.
Oral absorption of acitretin is optimal when given with food. For this reason, acitretin was given with food in all of the following trials. After administration of a single 50-mg oral dose of acitretin to 18 healthy subjects, maximum plasma concentrations ranged from 196 to 728 ng per mL (mean: 416 ng per mL) and were achieved in 2 to 5 hours (mean: 2.7 hours). The oral absorption of acitretin is linear and proportional with increasing doses from 25 to 100 mg. Approximately 72% (range: 47% to 109%) of the administered dose was absorbed after a single 50-mg dose of acitretin was given to 12 healthy subjects.
Acitretin is more than 99.9% bound to plasma proteins, primarily albumin.
For more Absorption, Distribution and Excretion (Complete) data for Acitretin (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
Following oral absorption, acitretin undergoes extensive metabolism and interconversion by simple isomerization to its 13-cis form (cis-acitretin). Both parent compound and isomer are further metabolized into chain-shortened breakdown products and conjugates, which are excreted.
Following oral absorption, acitretin undergoes extensive metabolism and interconversion by simple isomerization to its 13-cis form (cis-acitretin). The formation of cis-acitretin relative to parent compound is not altered by dose or fed/fast conditions of oral administration of acitretin. Both parent compound and isomer are further metabolized into chain-shortened breakdown products and conjugates, which are excreted. Following multiple-dose administration of acitretin, steady-state concentrations of acitretin and cis-acitretin in plasma are achieved within approximately 3 weeks.
... In the presence of ethanol the ethyl esterification of acitretin to etretinate proceeds via formation of acitretinoyl-CoA.

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Biological Half-Life
49 hours (range 33 to 96 hours)
... 10 patients with severe psoriasis were treated with 30 mg acitretin daily for 3 months. ... After discontinuation of therapy, the rate of elimination of both acitretin (half life range 1.0 to 25.4 days) and 13-cis-acitretin (half life range 1.5 to 25.7 days) was found to be related to the observed mean steady-state level of etretinate as evidenced by a longer terminal half life of patients with high levels of etretinate in plasma. ...
The terminal elimination half-life of acitretin following multiple-dose administration is 49 hours (range: 33 to 96 hours), and that of cis-acitretin under the same conditions is 63 hours (range: 28 to 157 hours).

Toxicity Summary
IDENTIFICATION AND USE: Acitretin is a keratolytic agent indicated for the treatment of severe psoriasis in adults. Acitretin has been used in a limited number of patients for the management of discoid lupus erythematosus. HUMAN STUDIES: Symptoms of overdose are identical to acute hypervitaminosis A, including headache and vertigo. Lipid elevations were reported in 25-50% of acitretin recipients. Elevations of triglycerides to concentrations associated with fatal fulminant pancreatitis are rare; however, cases have been reported with acitretin. Rare cases of pancreatitis without hypertriglyceridemia also have been reported. The case of a female psoriatic patient with angioedema (without urticaria) due to oral acitretin was reported. Acitretin should be considered as a possible cause of thrombotic stroke. n one reported case of overdose, a 32 year old male with Darier's disease took 525 mg single dose. He vomited several hours later but experienced no other ill effects. No decreases in sperm count or concentration and no changes in sperm motility or morphology were noted in 31 men (17 psoriatic subjects, 8 subjects with disorders of keratinization, and 6 healthy volunteers) given 30 to 50 mg per day of acitretin for at least 12 weeks. In these trials, no deleterious effects were seen on either testosterone production, LH, or FSH in any of the 31 men. No deleterious effects were seen on the hypothalamic-pituitary axis in any of the 18 men where it was measured. Acitretin is a known human teratogen, and there is a very high risk of severe birth defects if a patient becomes pregnant while receiving acitretin or upon drug discontinuance (birth defects have been reported 2 years or longer after the last dose of acitretin). Teratogenicity generally is characterized by malformations involving craniofacial, cardiovascular, skeletal, and CNS structures. Acitretin was evaluated for mutagenic potential in unscheduled DNA synthesis assay in human fibroblasts. No evidence of mutagenicity of acitretin was observed in this assay. ANIMAL STUDIES: An 80-week carcinogenesis study in mice has been completed with etretinate, the ethyl ester of acitretin. Blood level data obtained during this study demonstrated that etretinate was metabolized to acitretin and that blood levels of acitretin exceeded those of etretinate at all times studied. In the etretinate study, an increased incidence of blood vessel tumors (hemangiomas and hemangiosarcomas at several different sites) was noted in male, but not female, mice. A carcinogenesis study of acitretin in rats, at doses up to 2 mg per kg per day administered 7 days per week for 104 weeks, has been completed. There were no neoplastic lesions observed that were considered to have been related to treatment with acitretin. Chronic toxicity studies in dogs revealed testicular changes (reversible mild to moderate spermatogenic arrest and appearance of multinucleated giant cells) in the highest dosage group (50 then 30 mg/kg per day). In a fertility study in rats, the fertility of treated animals was not impaired at the highest dosage of acitretin tested, 3 mg per kg per day. Acitretin was evaluated for mutagenic potential in the Ames test, in the Chinese hamster (V79/HGPRT) assay, in unscheduled DNA synthesis assays using rat hepatocytes and in an in vivo mouse micronucleus assay. No evidence of mutagenicity of acitretin was demonstrated in any of these assays.

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Hepatotoxicity
Liver test abnormalities occur in up to one third of patients on acitretin, although marked elevations above three times the upper limit of normal occur in only 1% to 5%. These abnormalities are typically transient, not accompanied by symptoms and can resolve even with continuation of acitretin, but they may be associated with mild symptoms and require drug discontinuation in up to 4% of patients.
Acitretin can also cause clinically apparent liver injury with symptoms and jaundice. Although uncommon, acute liver injury from acitretin is well described and is estimated to occur in 0.1% to 0.5% of treated patients. The onset of injury can be as soon as one week or up to 9 months after starting therapy. The pattern of liver enzyme elevations is typically hepatocellular (Case 1), but cholestatic hepatitis due to acitretin has been reported (Case 2). Most cases resolve rapidly with stopping acitretin. Rash, fever, eosinophilia and other signs of hypersensitivity occur in many but not all cases; autoantibodies are rare. The injury is not at all like that of vitamin A and is not associated with fat accumulation in stellate cells. Because its potential for causing hepatotoxicity, routine monitoring of serum aminotransferase levels during acitretin therapy is recommended.
Likelihood score, acitretin: B (likely rare cause of clinically apparent liver injury).
A similar pattern of acute liver injury was reported with etretinate, a related retinoid that was previously used for psoriasis and acne, but was withdrawn from use in the United States in 1998.
Likelihood score, etretinate: B (highly likely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
A maternal acitretin dose of 0.65 mg/kg daily produced low levels in milk in one woman. Because there is no published experience with use of acitretin during breastfeeding, opinions vary on the advisability of breastfeeding during acitretin therapy. Various topical agents that are less likely to be absorbed by the mother may be preferred during breastfeeding, especially while nursing a newborn or preterm infant. Only water-miscible cream or gel products should be applied to the breast because ointments may expose the infant to high levels of mineral paraffins via licking.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
A review of adverse reaction reports on retinoids causing a breast reaction submitted to a French pharmacovigilance center found 8 cases of gynecomastia associated with acitretin use.

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Protein Binding
Over 99.9% bound to plasma proteins, primarily albumin.

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Interactions
Long-term immunosuppression in the organ transplant recipient (OTR) population places these individuals at higher risk of developing skin malignancies. Oral retinoids have become a useful tool for pharmacologic prophylaxis in the OTR population. Immunosuppressants that inhibit mTOR, such as sirolimus, may be used in combination with a systemic retinoid for chemoprophylaxis of cutaneous malignancies. We present the case of a male patient status post second renal transplant who developed an abrupt and unexpected rise in sirolimus levels to supra-therapeutic levels after initiation of prophylactic acitretin for innumerable squamous cell carcinomas (SCC). The sirolimus levels returned to baseline after cessation of acitretin. Systemic drug-drug interactions are an important phenomenon, especially in the solid OTR population. It is postulated that this interaction was mediated by acitretin inhibition of CYP3A4, the primary enzyme responsible for sirolimus metabolism. The Drug Interaction Probability Scale (DIPS) indicates this was a "probable" drug-drug interaction. To date, this interaction has not been reported in the literature. This case accentuates the importance of close monitoring of solid OTRs for adverse medication interactions when multiple medications are taken.
Concomitant administration of alcohol and acitretin resulted in formation of etretinate, a known human teratogen with a longer elimination half-life than acitretin; this interaction may increase the duration of teratogenic effects of acitretin. Concomitant use also may result in hepatotoxicity. Concomitant use of alcohol from any source should be avoided during and for 2 months after acitretin therapy cessation in women of childbearing potential.
Additive adverse effects (e.g., hypervitaminosis A) are possible in patients concomitantly receiving acitretin with vitamin A. Concomitant use is contraindicated.
There is an increased risk of hepatitis in patients concomitantly receiving acitretin and methotrexate. Concomitant use is contraindicated.
For more Interactions (Complete) data for Acitretin (15 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Mouse ip >4000 mg/kg (1 day)
LD50 Mouse ip 700 mg/kg (10 days)
LD50 Mouse ip 700 mg/kg (20 days)

[1]. A review of acitretin, a systemic retinoid for the treatment of psoriasis. Expert Opin Pharmacother. 2005 Aug;6(10):1725-34.

[2]. Effects of acitretin on spermatogenesis of rats. J Eur Acad Dermatol Venereol. 2006 Jul;20(6):689-92.

[3]. The Synthetic Retinoid Acitretin Increases IL-6 in the Central Nervous System of Alzheimer Disease Model Mice and Human Patients. Front Aging Neurosci. 2019 Jul 23;11:182.

All-trans-acitretin is an acitretin, a retinoid and an alpha,beta-unsaturated monocarboxylic acid. It has a role as a keratolytic drug.
An oral retinoid effective in the treatment of psoriasis. It is the major metabolite of etretinate with the advantage of a much shorter half-life when compared with etretinate.
Acitretin is a Retinoid.
Acitretin is a retinoid and vitamin A derivative currently used in the treatment of psoriasis. Acitretin, like many retinoids, can lead to increase in serum aminotransferase levels and has been implicated in cases of acute liver injury which can be severe and even fatal.
Acitretin is an orally-active metabolite of the synthetic aromatic retinoic acid agent etretinate with potential antineoplastic, chemopreventive, anti-psoratic, and embryotoxic properties. Acitretin activates nuclear retinoic acid receptors (RAR), resulting in induction of cell differentiation, inhibition of cell proliferation, and inhibition of tissue infiltration by inflammatory cells. This agent may also inhibit tumor angiogenesis. (NCI04)
An oral retinoid effective in the treatment of psoriasis. It is the major metabolite of ETRETINATE with the advantage of a much shorter half-life when compared with etretinate.

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Drug Indication
For the treatment of severe psoriasis in adults.
FDA Label

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Mechanism of Action
The mechanism of action of acitretin is unknown, however it is believed to work by targeting specific receptors (retinoid receptors such as RXR and RAR) in the skin which help normalize the growth cycle of skin cells.

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Therapeutic Uses
Keratolytic Agents
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Acitretin is included in the database.
Acitretin Capsules, USP are indicated for the treatment of severe psoriasis in adults. Because of significant adverse effects associated with its use, Acitretin Capsules, USP should be prescribed only by those knowledgeable in the systemic use of retinoids. In females of reproductive potential, Acitretin Capsules, USP should be reserved for non-pregnant patients who are unresponsive to other therapies or whose clinical condition contraindicates the use of other treatments /Included in US product labeling/
Acitretin has been used in a limited number of patients for the management of discoid lupus erythematosus; efficacy was similar to that of hydroxychloroquine, but adverse effects were more severe and frequent with acitretin. Further study is needed to establish the role of acitretin in treating this condition. /NOT included in US product labeling/
For more Therapeutic Uses (Complete) data for Acitretin (9 total), please visit the HSDB record page.

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Drug Warnings
/BOXED WARNING/ CONTRAINDICATIONS AND WARNINGS: Pregnancy. Acitretin must not be used by females who are pregnant, or who intend to become pregnant during therapy or at any time for at least 3 years following discontinuation of therapy. Acitretin also must not be used by females who may not use reliable contraception while undergoing treatment and for at least 3 years following discontinuation of treatment. Acitretin is a metabolite of etretinate (TEGISON), and major human fetal abnormalities have been reported with the administration of acitretin and etretinate. Potentially, any fetus exposed can be affected. Clinical evidence has shown that concurrent ingestion of acitretin and ethanol has been associated with the formation of etretinate, which has a significantly longer elimination half-life than acitretin. Because the longer elimination half-life of etretinate would increase the duration of teratogenic potential for female patients, ethanol must not be ingested by female patients of childbearing potential either during treatment with acitretin or for 2 months after cessation of therapy. This allows for elimination of acitretin, thus removing the substrate for transesterification to etretinate. The mechanism of the metabolic process for conversion of acitretin to etretinate has not been fully defined. It is not known whether substances other than ethanol are associated with transesterification. Acitretin has been shown to be embryotoxic and/or teratogenic in rabbits, mice, and rats at oral doses of 0.6, 3, and 15 mg per kg, respectively. These doses are approximately 0.2, 0.3, and 3 times the maximum recommended therapeutic dose, respectively, based on a mg-per-m 2 comparison. Major human fetal abnormalities associated with acitretin and/or etretinate administration have been reported including meningomyelocele; meningoencephalocele; multiple synostoses; facial dysmorphia; syndactyly; absence of terminal phalanges; malformations of hip, ankle, and forearm; low-set ears; high palate; decreased cranial volume; cardiovascular malformation; and alterations of the skull and cervical vertebrae. Acitretin should be prescribed only by those who have special competence in the diagnosis and treatment of severe psoriasis, are experienced in the use of systemic retinoids, and understand the risk of teratogenicity. Because of the teratogenicity of acitretin, a program called P.P.E.T., Pregnancy Prevention is Essential with Treatment, has been developed to educate women of childbearing potential and their healthcare providers about the serious risks associated with acitretin and to help prevent pregnancies from occurring with the use of this drug and for 3 years after its discontinuation.
/BOXED WARNING/ Hepatotoxicity: Of the 525 subjects treated in US clinical trials, 2 had clinical jaundice with elevated serum bilirubin and transaminases considered related to treatment with acitretin. Liver function test results in these subjects returned to normal after acitretin was discontinued. Two of the 1,289 subjects treated in European clinical trials developed biopsy-confirmed toxic hepatitis. A second biopsy in one of these subjects revealed nodule formation suggestive of cirrhosis. One subject in a Canadian clinical trial of 63 subjects developed a 3-fold increase of transaminases. A liver biopsy of this subject showed mild lobular disarray, multifocal hepatocyte loss, and mild triaditis of the portal tracts compatible with acute reversible hepatic injury. The subject's transaminase levels returned to normal 2 months after acitretin was discontinued. The potential of therapy with acitretin to induce hepatotoxicity was prospectively evaluated using liver biopsies in an open-label trial of 128 subjects. Pretreatment and posttreatment biopsies were available for 87 subjects. A comparison of liver biopsy findings before and after therapy revealed 49 (58%) subjects showed no change, 21 (25%) improved, and 14 (17%) subjects had a worsening of their liver biopsy status. For 6 subjects, the classification changed from class 0 (no pathology) to class I (normal fatty infiltration; nuclear variability and portal inflammation; both mild); for 7 subjects, the change was from class I to class II (fatty infiltration, nuclear variability, portal inflammation, and focal necrosis; all moderate to severe); and for 1 subject, the change was from class II to class IIIb (fibrosis, moderate to severe). No correlation could be found between liver function test result abnormalities and the change in liver biopsy status, and no cumulative dose relationship was found. Elevations of AST (SGOT), ALT (SGPT), GGT (GGTP), or LDH have occurred in approximately 1 in 3 subjects treated with acitretin. Of the 525 subjects treated in clinical trials in the US, treatment was discontinued in 20 (3.8%) due to elevated liver function test results. If hepatotoxicity is suspected during treatment with acitretin, the drug should be discontinued and the etiology further investigated. Ten of 652 subjects treated in US clinical trials of etretinate, of which acitretin is the active metabolite, had clinical or histologic hepatitis considered to be possibly or probably related to etretinate treatment. There have been reports of hepatitis-related deaths worldwide; a few of these subjects had received etretinate for a month or less before presenting with hepatic symptoms or signs.
Acitretin is a known human teratogen, and there is a very high risk of severe birth defects if a patient becomes pregnant while receiving acitretin or upon drug discontinuance (birth defects have been reported 2 years or longer after the last dose of acitretin). Teratogenicity generally is characterized by malformations involving craniofacial, cardiovascular, skeletal, and CNS structures. Use of acitretin is contraindicated during pregnancy. The drug must not be used in female patients who are or may become pregnant during acitretin therapy or within at least 3 years following drug discontinuance or in females who may not use reliable contraception during and for at least 3 years following cessation of therapy. If pregnancy occurs during therapy or at any time for at least 3 years following drug discontinuance, the clinician and patient should discuss the possible effects on the pregnancy.
Acitretin is distributed into milk; women receiving the drug should not breast-feed.
For more Drug Warnings (Complete) data for Acitretin (20 total), please visit the HSDB record page.

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Pharmacodynamics
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.

C21H26O3

326.43

326.188

55079-83-9

Acitretin sodium;925701-88-8

5284513

Light yellow to yellow solid powder

1.1±0.1 g/cm3

521.3±38.0 °C at 760 mmHg

228-230ºC

180.3±20.3 °C

0.0±1.4 mmHg at 25°C

1.570

5.73

1

3

6

24

539

0

CC1=CC(=C(C(=C1/C=C/C(=C/C=C/C(=C/C(=O)O)/C)/C)C)C)OC

IHUNBGSDBOWDMA-AQFIFDHZSA-N

InChI=1S/C21H26O3/c1-14(8-7-9-15(2)12-21(22)23)10-11-19-16(3)13-20(24-6)18(5)17(19)4/h7-13H,1-6H3,(H,22,23)/b9-7+,11-10+,14-8+,15-12+

(2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoic acid

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 mg/mL (6.13 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2 mg/mL (6.13 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2 mg/mL (6.13 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 20.0 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.)