9-Cis-Retinoic Acid

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Metabolite of Isotretinoin

Yellow fine needles from ethanol

Yellow powder

Insoluble in water

In ethanol, 7.01 mg/g at 25 °C

Breast Feeding; Lactation; Milk, Human; Antineoplastic Agents; Dermatologic Agents; Keratolytic Agents; Retinoids

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

189-190 °C

190-191 °C

Danger

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

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

Aggregated GHS information provided per 42 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including alitretinoin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Skin Irrit. 2 (100%)

Acute Tox. 4 (100%)

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Advice for firefighters: Wear self-contained breathing apparatus for fire fighting if necessary.

Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature -20 °C.

Store at 25 deg C (77 °F); excursions permitted to 15-30 °C (59-86 °F).

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber. Contaminated packaging: Dispose of as unused product.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided.

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.

Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Skin protection: Handle with gloves.

Body Protection: Impervious clothing. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

BACKGROUND: Based on in vitro data with isolated cytochrome P450 (CYP) isoenzymes, alitretinoin interacts only with CYP3A4, and the potential for drug-drug interactions is considered negligible. AIM: To confirm in humans the lack of potential interactions between CYP3A4 and alitretinoin in vivo. METHODS: This was a multiple-dose, open-label, parallel-group, single-centre study, which enrolled 54 healthy male volunteers aged 18-45 years. Subjects were divided into three groups, with 18 in each group: group 1 received either alitretinoin 30 mg and ketoconazole 200 mg, group 2 alitretinoin 30 mg and simvastatin 40 mg, and group 3 alitretinoin 30 mg and cyclosporin A 300-mg. RESULTS: At the highest therapeutic dose of 30 mg, alitretinoin had no significant effect on the pharmacokinetics (PK) of ketoconazole and cyclosporin A. There was a significant but not clinically relevant effect of simvastatin on the area under the curve (AUC) of plasma concentration vs. time and on maximum plasma concentration (C(max)) after repeated administration of alitretinoin. Exposure to simvastatin concomitantly with alitretinoin was decreased by 16% for AUC and 23% for C(max). The CYP3A4 +/- PgP substrates of simvastatin and cyclosporin A did not affect the single or repeated dose PK of alitretinoin. The strong CYP3A4/PgP inhibitor ketoconazole led to significant increases in both AUC and C(max) values for alitretinoin. CONCLUSIONS: Single and repeated doses of alitretinoin do not alter the PK of cyclosporin A and ketoconazole. Simvastatin levels were slightly but significantly reduced by co-administration of alitretinoin. Substrates of CYP3A4 did not affect the PK of alitretinoin. However, ketoconazole significantly increased the plasma levels of alitretinoin, therefore, co-administration with CYP3A4 inhibitors such as ketoconazole may require a dose reduction of alitretinoin.

Patients who are applying Panretin gel should not concurrently use products that contain DEET (N,N-diethyl-m-toluamide), a common component of insect repellent products. Animal toxicology studies showed increased DEET toxicity when DEET was included as part of the formulation.

IDENTIFICATION AND USE: Alitretinoin is an antineoplastic agent, used for topical treatment of cutaneous lesions in patients with AIDS-related Kaposi's sarcoma. HUMAN STUDIES: The most common adverse events were typical class effects of oral retinoids including headache, flushing, and skin disorders. There was a case of sensitization to alitretinoin reported in the literature. It was not found to be clastogenic in vitro in chromosome aberration test in human lymphocytes. ANIMAL STUDIES: Administration of alitretinoin to pregnant mice at 3 mg/kg on day 7.5 induced a 12% resorption rate and 0% exencephaly in 58 implants. In the 51 live fetuses that were given alitretinoin, there were 9 cases of microphthalmia and 6 cases of anophthalmia. Both the resorption and exencephaly rates indicate that alitretinoin is less potent than trans retinoic acid for these endpoints. An increased incidence of fused sternebrae and limb and craniofacial defects occurred in rabbits given oral doses of 0.5 mg/kg/day during the period of organogenesis. Limb and craniofacial defects also occurred in mice given a single oral dose of 50 mg/kg on day 11 of gestation. Oral alitretinoin was embryocidal, as indicated by early resorptions and post-implantation loss when it was given during the period of organogenesis to rabbits at doses of 1.5 mg/kg/day and to rats at doses of 5 mg/kg/day. Alitretinoin was not found to be mutagenic in in vitro tests including the Chinese hamster ovary cell HGPRT mutation assay. It was not found to be clastogenic in vivo (mouse micronucleus test). ECOTOXICITY STUDIES: In the Japanese flounder Paralichthys olivaceus, at 6-9 days post-hatching, all retinoic acid isomers (including alitretinoin) exerted toxic effects on the skeletal systems, mainly through the RAR pathway.

Tretinoin binds to alpha, beta, and gamma retinoic acid receptors (RARs). RAR-alpha and RAR-beta have been associated with the development of acute promyelocytic leukemia and squamous cell cancers, respectively. RAR-gamma is associated with retinoid effects on mucocutaneous tissues and bone. Although the exact mechanism of action of tretinoin is unknown, current evidence suggests that the effectiveness of tretinoin in acne is due primarily to its ability to modify abnormal follicular keratinization. Comedones form in follicles with an excess of keratinized epithelial cells. Tretinoin promotes detachment of cornified cells and the enhanced shedding of corneocytes from the follicle. By increasing the mitotic activity of follicular epithelia, tretinoin also increases the turnover rate of thin, loosely-adherent corneocytes. Through these actions, the comedo contents are extruded and the formation of the microcomedo, the precursor lesion of acne vulgaris, is reduced. Tretinoin is not a cytolytic agent but instead induces cytodifferentiation and decreased proliferation of APL cells in culture and in vivo. When Tretinoin is given systemically to APL patients, tretinoin treatment produces an initial maturation of the primitive promyelocytes derived from the leukemic clone, followed by a repopulation of the bone marrow and peripheral blood by normal, polyclonal hematopoietic cells in patients achieving complete remission (CR). The exact mechanism of action of tretinoin in APL is unknown.

/AQUATIC SPECIES/ Previously reported ...characteristic deformities were induced by retinoic acid (RA) treatment of the Japanese flounder, Paralichthys olivaceus, at 6-9 days post-hatching (dph). To evaluate the toxic potency of nuclear retinoid receptors in induction of deformities by RA, ...the effects of retinoic acid isomers on postembryonic development of this species /were investigated/. Larvae were exposed to either 25 nM of all-trans RA (atRA), 9-cis RA (9cRA) or 13-cis RA (13cRA) at 6-9 dph. All RA isomers induced deformities in the lower jaw, caudal fin and vertebrae. In the lower jaw, growth retardation of the dentary was evident. In the vertebrae, the major abnormalities were hypertrophy of the centrum, central fusion, and an increase in the number of abdominal vertebrae. Caudal fin deformities included deformity of caudal bone complex and absence of the entire caudal fin. The absence of the hypural primordium at 12 dph was the first sign of abnormality in caudal fin development, and resulted in complete blocking of the caudal fin development. Among the RA isomers, atRA induced the most severe deformity in all skeletons examined. Retinoic acid receptor (RAR) expression was activated by atRA and 9cRA, and pitx2 expression was inhibited in the lower jaw by atRA and 9cRA. Vitamin D receptor (VDR) expression was specifically inhibited by atRA treatment, suggesting that RA inhibits the lower jaw growth by suppressing the expression of these genes. These results suggest that RA exerted toxic effects on the skeletal systems, mainly through the RAR pathway.

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of February 4, 2019: http://actor.epa.gov/dashboard/]

/SIGNS AND SYMPTOMS/ BACKGROUND: The link between isotretinoin, treatment of a severe form of acne, and psychiatric disorders remains controversial, as acne itself could explain the occurrence of psychiatric disorders. This study aims at assessing the disproportionality of psychiatric adverse events reported with isotretinoin in the French National PharmacoVigilance Database, compared with other systemic acne treatments and systemic retinoids. MATERIALS AND METHODS: Data were extracted from the French National PharmacoVigilance Database for systemic acne treatments, systemic retinoids and drugs used as comparators. Each report was subjected to double-blind analysis by two psychiatric experts. A disproportionality analysis was performed, calculating the number of psychiatric ADRs divided by the total number of notifications for each drug of interest. RESULTS: Concerning acne systemic treatments: all 71 reports of severe psychiatric disorders involved isotretinoin, the highest proportion of mild/moderate psychiatric adverse events was reported with isotretinoin (14.1%). Among systemic retinoids, the highest proportion of severe and mild/moderate psychiatric events occurred with isotretinoin and alitretinoin. CONCLUSION: Our study raises the hypothesis that psychiatric disorders associated with isotretinoin are related to a class effect of retinoids, as a signal emerges for alitretinoin. Complementary studies are necessary to estimate the risk and further determine at-risk populations.

/SIGNS AND SYMPTOMS/ Alitretinoin is a unique retinoid authorized for the treatment of adults with severe chronic hand eczema (CHE) refractory to potent topical steroids. The most common adverse events (AEs) were typical class effects of oral retinoids including headache, flushing and skin disorders. To our knowledge, there are no cases of sensitization to alitretinoin reported in literature. We present a case of sensitization to alitretinoin.

/GENOTOXICITY/ It was not found to be clastogenic in vitro (chromosome aberration test in human lymphocytes)...

/ALTERNATIVE and IN VITRO TESTS/ Functional studies indicate that essential cellular processes are controlled by Vitamin A derivatives. Among these the retinoic acid isoforms, all-trans- and 9-cis (9cRA), regulate the expression of various genes in both physiological and pathological conditions. Using several in vitro experimental models such as pancreatic beta-cells, pre-adipocytes and breast cancer cells with different phenotypes, we demonstrated the capability of 9cRA to modulate myotrophin (Mtpn) and miR-375 expressions. The 9cRA effect in pancreatic beta-cells line INS-1 832/13 point out a decreased expression of Mptn at both mRNA and protein levels associated to a concomitant increase of miR-375. We also studied the effect of this molecule on 3T3-L1 pre-adipocytes cells demonstrating a down-regulation of Mtpn and a dramatic increase of miR-375. Moreover, in the in vitro breast cancer model such as MDA-MB-231 and MCF-7 cells, 9cRA showed different effect on both Mtpn and miR-375 expression. In INS-1 832/13, 3T3-L1 pre-adipocytes and MCF-7 but not in MDA-MB-231, the effect of 9cRA on Mptn gene expression and its miR was under the control of RARs and RXRs receptors, as revealed by the exposure of these cell line to LE540 or HX603 receptor antagonists. In our findings 9cRA emerges has a hormone with a regulatory action on miR-375 that in most cases interfere with Mtpn expression.

For more Human Toxicity Excerpts (Complete) data for Alitretinoin (7 total), please visit the HSDB record page.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Experiments in vitro with cultured rat conceptuses have shown that all-trans-retinoic acid (TRA) is 7-10 times more potent than 13-cis-retinoic acid (13-CRA) either when added to the culture medium (300 ng TRA/mL culture medium ...) or when microinjected (300 ng TRA/mL amniotic fluid ...). Major defects involved the branchial arches and somites. Using HPLC analyses, it was shown that TRA is ultimately responsible for the dysmorphogenic effects produced by 13-CRA. In the present study, we show that intraamniotic microinjections of 9-cis-retinoic acid (9-CRA, 300 ng/mL amniotic fluid) elicited increases in branchial arch and somite defect quantitatively similar (30-50%) to those produced by TRA at the same concentrations (300 ng TRA/mL amniotic fluid). Additions of the same concentrations to the culture medium produced virtually identical effects. In addition, 9-CRA produced a 33% incidence of cephalic schisis as compared with a 5% incidence elicited by TRA. At 600 ng/mL culture medium, 9-CRA also produced a 53% incidence of cardiac anomalies. HPLC analyses indicated that conceptal biotransformation of microinjected retinoids had occurred. Six hrs after addition of 300 ng TRA/mL culture medium, 13-CRA, TRA and 4-oxo-RA were detected in embryonic tissues. Six hrs after addition of 500 ng 13-CRA/mL culture medium, 13-CRA, TRA and 13-cis-retinoyl-beta-glucuronide were detected in embryos. At 2.0, 3.5 and 4.5 hrs after addition of 300 ng 9-CRA/mL culture medium, 9-CRA and small quantities of 13-CRA were detected in embryos and, after 6 hrs, TRA was also detected. The results indicated that 9-CRA is a direct-acting dysmorphogen, equipotent to TRA.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ 9-cis Retinoic acid (9cRA) is proposed to be the endogenous ligand for the retinoid X receptors (RXRs), and studies have demonstrated that this retinoid binds to the alpha, beta, and gamma-types of the RXRs. In addition, 9cRA binds to the alpha, beta, and gamma forms of the retinoic acid receptors (RARs) with approximately equal affinity for these receptors as all-trans retinoic acid (trRA). If the teratogenic action of these retinoids is receptor mediated, then the fact that the 9cRA activates a family of receptors in addition to the RARs, provides the rationale for comparing the relative potency of 9cRA and trRA. In vivo single intraperitoneal administration of trRA to C57BL/6NCrlBR mice at half-day intervals from gestational day 6.5 through 8.5 showed that the most sensitive time for the induction of exencephaly was day 7.5. At a trRA dose of 3 mg/kg on day 7.5, embryolethality was 32% and exencephaly was 47% in a total of 94 implantation sites. Alternatively, administration of 9cRA at 3 mg/kg on day 7.5 induced a 12% resorption rate and 0% exencephaly in 58 C57BL/6N implants. In the 51 live fetuses that were given 9cRA, there were 9 cases of microphthalmia and 6 cases of anophthalmia. Both the resorption and exencephaly rates indicate that 9cRA is less potent than trRA for these endpoints. Factors that may contribute to the lower potency of 9cRA than trRA for embryolethality and exencephaly are as follows: (1) lower binding affinity of 9cRA than trRA for the RAR-gamma, (2) 9cRA does not bind to CRABP I or II in contrast to trRA, (3) differential transplacental/embryonic distribution, and (4) RXRs may not require a ligand for certain receptor-mediated events.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ The present study determines the relative developmental toxicity potencies of retinoids in the embryonic stem (ES)-D3 cell differentiation assay of the embryonic stem cell test, and compares the outcomes with their relative potencies in in vivo and two other in vitro assays for developmental toxicity. The results reveal that the potency ranking obtained in the ES-D3 cell differentiation assay is similar to the reported potency rankings in the two other in vitro assays for developmental toxicity. TTNPB ((E)-4[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid) was the most potent retinoid, whereas etretinate and retinol had the lowest potency. All-trans-retinoic acid, 13-cis-retinoic acid, 9-cis-retinoic acid and acitretin showed an intermediate potency. In vivo potency rankings of the developmental toxicity of retinoids appear to be dependent on the species and/or exposure regimens used. The obtained in vitro potency ranking does not completely correspond with the in vivo potency rankings, although TTNPB is correctly predicted to be the most potent and retinol the least potent congener. The lack of in vivo kinetic processes in the ES-D3 cell differentiation assay might explain the deviating potency predictions of some retinoids. Therefore, knowledge on the species-dependent in vivo kinetics is essential when using in vitro toxicity data for the estimation of in vivo developmental toxicity potencies within series of related compounds.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ An increased incidence of fused sternebrae and limb and craniofacial defects occurred in rabbits given oral doses of 0.5 mg/kg/day (about five times the estimated daily human topical dose on a mg/sq m basis, assuming complete systemic absorption of 9-cis-retinoic acid, when Panretin gel is administered as a 60 g tube over 1 month in a 60 kg human) during the period of organogenesis.

For more Non-Human Toxicity Excerpts (Complete) data for Alitretinoin (14 total), please visit the HSDB record page.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) or lorazepam (Ativan) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

Emergency and supportive measures ... Extravasation. Immediately stop the infusion and withdraw as much fluid as possible by applying negative pressure on the syringe. Elevate the affected limb. Surgical intervention may be necessary. Specific treatment recommendations vary by institutional preferences ... Do not use DMSO for patients receiving dexrazoxane. For most chemotherapeutic agents, apply cool compresses to the extravasation site for 15 minutes 4 times daily for 2-3 days. Do not use cool compresses for vinca alkaloids (eg vinblastine, vincristine). Apply warn compresses/heating pad intermittently (15-30 minutes times a day) for 1-2 days specifically for vinblastine, vincristine, and vinorelbine. Do not apply heat for anthracyclines. Application of both cool and warm compresses has been recommended for carboplatin, carmustine, dacarbazine, docetaxel, etoposide, fluorouracil, methotrexate, oxaliplatin, and paclitaxel. There is no justificaiton for injeciton of hydrocortisone or sodium bicarbonate. /Antineoplastics/

For more Antidote and Emergency Treatment (Complete) data for Alitretinoin (6 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including alitretinoin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

L - Antineoplastic and immunomodulating agents

D - Dermatologicals

QD - Dermatologicals

QL - Antineoplastic and immunomodulating agents

Alitretinoin (9-<i>cis</i>-retinoic acid) is a naturally-occurring endogenous retinoid indicated for topical treatment of cutaneous lesions in patients with AIDS-related Kaposi's sarcoma. Alitretinoin inhibits the growth of Kaposi's sarcoma (KS) cells <i>in vitro</i>.

Alitretinoin binds to and activates all known intracellular retinoid receptor subtypes (RARa, RARb, RARg, RXRa, RXRb and RXRg). Once activated these receptors function as transcription factors that regulate the expression of genes that control the process of cellular differentiation and proliferation in both normal and neoplastic cells.

Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) mediate the effects of retinoids on gene expression by binding to response elements in retinoid-sensitive genes. RAR- but not RXR-selective retinoids were found in many previous studies to suppress the growth of various cells, implicating RXR-RAR in these effects. ... RXR-selective retinoids inhibited DNA synthesis in squamous carcinoma 1483 cells transfected with RXRalpha but not with RARs. Ligand-induced transcription of the reporter luciferase gene via the activation of RXR-RXR but not RXR-RAR correlated with growth suppression. Studies with RXRalpha deletion mutants indicated that the DNA binding and the ligand binding domains are essential for mediating growth inhibition. A point mutation in the ligand binding domain (L430F) that decreased RXRalpha homodimerization compromised its growth inhibitory function. Further, RXRalpha mutant (F313A), which functions as a constitutively active receptor, inhibited DNA synthesis in the absence of ligand. These results demonstrate that RXR homodimer activation leads to growth inhibition and suggest that transfection of RXRalpha and treatment with RXR-selective retinoids or the transfection of constitutively activated RXRalpha mutant alone may have a therapeutic potential. /Retinoids/

The interaction of retinoid X receptor alpha with 9-cis-retinoic acid was studied ... . Transient kinetic analyses of this interaction suggest a two-step binding mechanism involving a rapid, enthalpically driven pre-equilibrium followed by a slower, entropically driven reaction that may arise from a conformational change within the ligand binding domain of the receptor. The assignment of this kinetic mechanism was supported by agreement between the overall equilibrium constant, Kov, derived from kinetic studies with that determined by equilibrium fluorescence titrations. Although these analyses do not preclude ligand-induced alteration in the oligomerization state of the receptor in solution, the simplest model that can be applied to these data involves the stoichiometric interaction of 9-cis-retinoic acid with retinoid X receptor alpha monomers.

Although there are no detectable plasma concentrations of 9-cis-retinoic acid metabolites after topical application of Panretin gel, in vitro studies indicate that the drug is metabolized to 4-hydroxy-9-cis-retinoic acid and 4-oxo-9-cis-retinoic acid by CYP 2C9, 3A4, 1A1, and 1A2 enzymes. In vivo, 4-oxo-9-cis-retinoic acid is the major circulating metabolite following oral administration of 9-cis-retinoic acid.

4-hydroxy-9-cis-retinals is a known human metabolite of 9-cis-retinal.

Hepatic Half Life: 0.5-2 hours

1UA8E65KDZ

ALITRETINOIN

Established Pharmacologic Class [EPC] - Retinoid

Chemical Structure [CS] - Retinoids

Alitretinoin is a Retinoid.

ALITRETINOIN

Substances that inhibit or prevent the proliferation of NEOPLASMS.

Drugs used to treat or prevent skin disorders or for the routine care of skin.

BACKGROUND: Previous studies have shown that concomitant administration of food may enhance the bioavailability of oral retinoids. AIM: To assess the influence of food on the pharmacokinetics (PK) of alitretinoin after a single oral dose. METHODS: This was a single-dose, open-label, randomized, crossover study, which enrolled 30 healthy men, aged 18-44 years. Subjects received sequential doses of alitretinoin 40 mg either after fasting (treatment A) or 5 min after completion of a standard breakfast (treatment B), with the dosing sequence randomized (A/B or B/A). The washout period between the two doses was 1 week. Plasma concentrations over time were plotted and standard PK variables [area under the curve (AUC) of plasma concentration vs. time, maximum plasma concentration (C(max)), time to maximum plasma concentration (t(max)) and elimination half-life (t(1/2)] were determined. RESULTS: Drug exposure was markedly increased when alitretinoin was taken with food compared with fasting, and there were significant increases in mean C(max) (82.8 vs.25.4 ng/mL, respectively) and AUC (220.2 vs. 55.7 ng/mL/hr). The delaying effect of food on t(max) was less marked (median of 3.0 vs. 2.0 h). Administration with food also increased exposure to drug metabolites. Variability in exposure was markedly reduced if alitretinoin was taken with vs. without food (percentage coefficient of variation 40% vs. 74% for AUC; 49% vs. 85% for C(max)). Alitretinoin was generally well tolerated, with typical retinoid adverse reactions, mostly comprising headache. CONCLUSIONS: Intake of alitretinoin with food substantially increased the bioavailability of alitretinoin, but variability in exposure was reduced. Consequently, oral alitretinoin should be taken with food as outlined in the manufacturer's summary of product characteristics.

BACKGROUND: Alitretinoin, like all retinoids, is teratogenic, and can only be given to women of childbearing potential if pregnancy is excluded and a strict contraceptive programme is followed. AIM: This study was designed to determine whether alitretinoin in the semen of men treated with alitretinoin poses a teratogenic risk to their female partners. METHODS: In total, 24 healthy men aged 18-45 years received alitretinoin 20 mg (n = 12) or 40 mg (n = 12), once daily for 14 days. Subjects in the 40 mg dose group provided ejaculate at baseline, on day 1, before and approximately 4 hr after dosing on day 2, and at follow-up on study day 21 (+/- 2). RESULTS: Alitretinoin and 4-oxo-alitretinoin were detected in 11 of the 12 semen samples. The highest level of alitretinoin in semen was 7.92 ng/mL. Assuming an ejaculate volume of 10 mL, the amount of drug transferred in semen would be about 80 ng, 1/375,000 of a single 30 mg capsule. Complete absorption of 80 ng of alitretinoin from semen, presuming a volume of distribution confined to 5 L of circulating blood in the partner, would lead to an increase in plasma alitretinoin concentration of 0.016 ng/mL, which appears to be negligible compared with measured endogenous plasma levels. Increases in plasma levels of related retinoids are also negligible. CONCLUSIONS: Alitretinoin in the semen of men receiving up to 40 mg of oral alitretinoin per day is unlikely to be associated with teratogenic risk in their female partners. Barrier contraception is therefore not required for men taking alitretinoin.

/MILK/ It is not known whether alitretinoin or its metabolites are excreted in human milk.

Limited data indicate that alitretinoin is not substantially absorbed systemically following topical application of the drug.

MEDICATION

Antineoplastic Agents

Use (kg; approx.) in Germany (2009): >10

For the the induction of remission in patients with acute promyelocytic leukemia (APL), French-American-British (FAB) classification M3 (including the M3 variant); For the topical treatment of acne vulgaris, flat warts and other skin conditions (psoriasis, ichthyosis congenita, icthyosis vulgaris, lamellar icthyosis, keratosis palmaris et plantaris, epidermolytic hyperkeratosis, senile comedones, senile keratosis, keratosis follicularis (Darier's disease), and basal cell carcinomas.); For palliative therapy to improve fine wrinkling, mottled hyperpigmentation, roughness associated with photodamage.