Isotretinoin

Pharmaceuticals -> Listed in ZINC15

Pharmaceutical

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals

Yellow crystals or reddish-orange plates from isopropyl alcohol

Yellowish to orange crystalline powder

less than 1 mg/mL at 72 °F (NTP, 1992)

0.00477mg/mL

Insoluble in water

Sparingly soluble in alcohol

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

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

372 to 374 °F (NTP, 1992)

189-190

174-175 °C

Cis-retinoic acid is a yellow-orange to orange crystalline powder; orange-brown chunky solid. (NTP, 1992)

Solid

5.15

~4

Danger

H315 (30.7%): 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 153 reports by companies from 12 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

H315: Causes skin irritation [Warning Skin corrosion/irritation]

Hazard Traits - Developmental Toxicity

Isotretinoin: Does not have an individual approval but may be used under an appropriate group standard

SYMPTOMS: Symptoms of exposure to this compound may include dryness and itching of the skin and conjunctivitis. It can also cause pruritus, epistaxis, dry nose and mouth, rash, temporary thinning of the hair, cheilitis, fatigue, skin fragility, skeletal hyperstosis, musculoskeletal symptoms and chest pain. Other symptoms, rarely seen, include peeling of the palms and soles, skin infections, nonspecific urogenital findings, nonspecific gastrointestinal symptoms and increased susceptibility to sunburn. This compound has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension) characterized by the following symptoms: headache, papilledema, nausea, vomiting and visual disturbances. It can also cause fetal abnormalities if ingested while pregnant. Other symptoms include ocular irritation, blurred vision, arthralgias, facial dermatitis, xerosis, minor nosebleed inflamed urethral meatus and urethritis.

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

An organic acid and unsaturated aliphatic hydrocarbon. Carboxylic acids donate hydrogen ions if a base is present to accept them. They react in this way with all bases, both organic (for example, the amines) and inorganic. Their reactions with bases, called "neutralizations", are accompanied by the evolution of substantial amounts of heat. Neutralization between an acid and a base produces water plus a salt. Insoluble carboxylic acids react with solutions of cyanides to cause the release of gaseous hydrogen cyanide. Flammable and/or toxic gases and heat are generated by the reaction of carboxylic acids with diazo compounds, dithiocarbamates, isocyanates, mercaptans, nitrides, and sulfides. Carboxylic acids, especially in aqueous solution, also react with sulfites, nitrites, thiosulfates (to give H2S and SO3), dithionites (SO2), to generate flammable and/or toxic gases and heat. Their reaction with carbonates and bicarbonates generates a harmless gas (carbon dioxide) but still heat. Like other organic compounds, carboxylic acids can be oxidized by strong oxidizing agents and reduced by strong reducing agents. These reactions generate heat. A wide variety of products is possible. Like other acids, carboxylic acids may initiate polymerization reactions; like other acids, they often catalyze (increase the rate of) chemical reactions.

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

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. Light sensitive.

Store at 20 deg to 25 °C (68 deg to 77 °F). Protect from light.

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.

SMALL SPILLS AND LEAKAGE: If a spill of this chemical occurs, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with acetone and transfer the dampened material to a suitable container. Use absorbent paper dampened with acetone to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with acetone followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

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.

For more Preventive Measures (Complete) data for 13-cis-Retinoic acid (7 total), please visit the HSDB record page.

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

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).

The FDA has recommended strengthening of the isotretinoin riskMAP to include mandatory registration of all patients, and mandatory linkage of negative pregnancy testing to prescription dispensing for female patients of childbearing potential. The new program will link prescribers, patients and pharmacies through a single centralized registry. The registry, or clearinghouse, will confirm that an appropriately timed pregnancy test is negative prior to authorizing the dispensing of an isotretinoin prescription for a female patient who is capable of becoming pregnant, and that informed consent, counseling, and patient education have occurred. The tentative date for implementation is July 2005.

Because of the potential for additive adverse effects, patients receiving isotretinoin should be warned to avoid concomitant use of preparations containing vitamin A or its derivatives.

Isotretinoin increased the concn of both haloperidol and reduced haloperidol in serum, red blood cells, and brain. However, the dose dependence and degree of the effect varied significantly across tissues.

Because some cases of pseudotumor cerebri (benign intracranial hypertension) associated with use of isotretinoin have involved patients also receiving tetracycline or minocycline, which have also been reported to cause increased intracranial pressure, such concomitant use of isotretinoin and tetracyclines should be avoided.

Although clinical studies have not been conducted to evaluate the effects on bone loss when phenytoin, which is known to cause osteomalacia, and isotretinoin are used concurrently, the manufacturers recommend exercising caution when these 2 drugs are used concomitantly. Isotretinoin has not been shown in vitro or in vivo to alter the pharmacokinetics of phenytoin.

For more Interactions (Complete) data for 13-cis-Retinoic acid (6 total), please visit the HSDB record page.

EC50; Species: Xenopus laevis (African clawed frog) embryo; Conditions: freshwater, renewal; Concentration: 0.002 mg/L for 96 hr; Effect: abnormal morphology /formulation/

LC50; Species: Xenopus laevis (African clawed frog) embryo; Conditions: freshwater, renewal; Concentration: 0.018 mg/L for 96 hr /formulation/

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 2.0X10+4(SRC), determined from a structure estimation method(2), indicates that 13-cis-retinoic acid is expected to be immobile in soil(SRC). The estimated pKa of 13-cis-retinoic acid is 5(3), indicating that this compound will exist partially in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of the neutral species of 13-cis-retinoic acid from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 9.5X10-6 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). However, adsorption to soil is expected to attenuate volatilization(SRC). 13-cis-Retinoic acid is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.0X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2018).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 2.0X10+4(SRC), determined from a structure estimation method(2), indicates that 13-cis-retinoic acid is expected to adsorb to suspended solids and sediment(SRC). Volatilization of the neutral species from water surfaces is expected(3) based upon an estimated Henry's Law constant of 9.5X10-6 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 7 and 55 days, respectively(SRC). However, volatilization from water surfaces is expected to be attenuated by adsorption to suspended solids and sediment in the water column. The volatilization half-life from a model pond is about 14 years when adsorption is considered(4). An estimated pKa of 5(5) indicates 13-cis-retinoic acid will exist partially in the anion form at pH values of 5 to 9 and, therefore, volatilization of the anion from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(6), an estimated BCF of 56(SRC), from a log Kow of 6.30 for analogous all-trans-retinoic acid(7) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data in water were not available(SRC, 2018).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 13-cis-retinoic acid, which has an estimated vapor pressure of 1.0X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase 13-cis-retinoic acid is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 1.3 hrs(SRC), calculated from its rate constant of 2.9X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Vapor-phase 13-cis-retinoic acid is degraded in the atmosphere by reaction with ozone(SRC); the half-life for this reaction in air is estimated to be 1.5 hrs(SRC), calculated from its rate constant of 1.8X10-16 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Particulate-phase 13-cis-retinoic acid may be removed from the air by wet and dry deposition(SRC). 13-cis-Retinoic acid absorbs UV light at wavelength 354 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Cheilitis (dry lips) is the most common dose-dependent adverse effect, affecting approximately 90% of patients taking isotretinoin. Other common adverse effects of isotretinoin include xerosis (dry skin), xerostomia (dry mouth), rhinitis sicca (dry nose), and photosensitivity. Before starting medication, the patient should be educated on the importance of sun protection, skin moisturizers, and the use of barriers. Patients should also avoid all skin resurfacing procedures, such as waxing, dermabrasion, and laser therapy, during treatment and for at least 6 months after treatment to prevent skin irritation and scarring.

IDENTIFICATION AND USE: 13-cis-Retinoic acid (Isotretinoin) is a dermatological agent. HUMAN STUDIES: Anaphylactic reactions and other allergic reactions have been reported. Cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement (including renal) have been reported. Acute pancreatitis, including rare cases of fatal hemorrhagic pancreatitis, has been reported in patients with elevated or normal serum triglyceride concentrations receiving isotretinoin. Skeletal abnormalities, similar to those occurring with high dosages of systemically administered vitamin A, have occurred in patients receiving isotretinoin therapy. Some evidence suggests that long-term, high-dosage, or multiple courses of isotretinoin therapy may have more of an effect on the musculoskeletal system than a single course of therapy. Between October 1982 and June 1985 the Adverse Drug Reaction Reporting System received reports of 104 suspected adverse reactions occurring in 93 patients who took isotretinoin. Adverse reactions involving the skin and mucous membranes, central nervous system, musculoskeletal system, pregnancy, and eyes were most commonly reported. Severe headache was the most frequently reported adverse reaction. Isotretinoin ranks in the top 10 of the US Food and Drug Administration's database of drugs associated with reports of depression and suicide attempts. However, this association is still controversial because up to 5.6% of patients with moderate acne may have pre-existing suicidal ideations, improvement of acne often reduces associated depression, and isotretinoin users are reportedly no more likely than those taking antibiotics for acne to have depression or commit suicide. Despite extensive precautions for its use, isotretinoin remains a cause of major birth defects, including sensorineural, conductive or mixed hearing loss. There is a report of a newborn with asymmetric crying face and other anomalies whose mother had taken isotretinoin during the first month of pregnancy. Two infants with prominent frontal bossing, hydrocephalus, microphthalmia, and small, malformed, low-set, undifferentiated ears were born to mothers who had taken isotretinoin in the first trimester of pregnancy. A Dandy-Walker malformation, microcephaly, hypertelorism, small ear canals, cleft palate, small mouth, and congenital heart disease were also observed. Isotretinoin is a potent teratogen in man. Maternal ingestion early in pregnancy leads to a distinct clinical pattern of anomalies. In human volunteers and patients, one major blood metabolite of isotretinoin is 4-oxo-isotretinoin which undergoes slower elimination than isotretinoin and may itself be a participant in teratogenesis. ANIMAL STUDIES: In male and female rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day for greater than 18 months, there was a dose-related increased incidence of pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia was also increased at the higher dosage in both sexes. In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks at dosages of 20 or 60 mg/kg/day. In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at oral dosages of isotretinoin of 2, 8, or 32 mg/kg/day. A clinical dose (1 mg/kg/day) of the drug in mice significantly reduces cell proliferation in the hippocampus and the subventricular zone, suppresses hippocampal neurogenesis, and severely disrupts capacity to learn a spatial radial maze task. ECOTOXICITY STUDIES: Japanese flounder, Paralichthys olivaceus, at 6-9 days post-hatching, all retinoic acid 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 was the first sign of abnormality in caudal fin development, and resulted in complete blocking of the caudal fin development.

Signs and Symptoms of Overdose

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.

The following link will take the user to the National Toxicology Program (NTP) Test Status of Agents Search page, which tabulates the results and current status of tests such as "Short-Term Toxicity Studies", "Long-term Carcinogenicity Studies", "Developmental Studies", "Genetic Toxicology Studies", etc., performed with this chemical. Testing status for 13-cis-retinoic acid is available.[Available from, as of February 1, 2019: https://ntpsearch.niehs.nih.gov/?e=True&ContentType=Testing+Status]

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/]

Workers who are potentially exposed to chemical hazards should be monitored in a systematic program of medical surveillance intended to prevent occupational injury and disease. ...For detection and control of work-related health effects, job-specific medical evaluations should be performed, as follows: before job placement; periodically during employment; following acute exposures; and at the time of job termination or transfer (exit examination) /Hazardous drugs not in solid final form/.

REPRODUCTIVE ISSUES. The examining physician should consider the reproductive status of employees and inform them regarding relevant reproductive issues. The reproductive toxicity of hazardous drugs should be carefully explained to all workers who will be exposed to these chemicals, and is required for those chemicals covered by the Hazard Communication Standard. ... The facility should have a policy regarding reproductive toxicity of hazardous drugs and worker exposure in male and female employees and should follow that policy /Hazardous drugs not in solid final form/.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of 13-cis-retinoic acid can be estimated to be 2.0X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that 13-cis-retinoic acid is expected to be immobile in soil. The estimated pKa of 13-cis-retinoic acid is 5(3), indicating that this compound will exist partially in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

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

D10BA01

D - Dermatologicals

D - Dermatologicals

QD - Dermatologicals

QD - Dermatologicals

Isotretinoin produces its effects through altering progress through the cell cycle, cell differentiation, survival, and apoptosis. These actions reduce sebum production, preventing the blockage of pores, and growth of acne causing bacteria. Isotretinoin and 4-oxo-isotretinoin both significantly reduce the production of sebum. Isotretinoin has little to no affinity for retinol binding proteins (RBPs) and retinoic acid nuclear receptors (RARs). Tretinoin and 4-oxo-tretinion bind to the RAR-γ receptor, which is suspected to be part of the action of acne treatment by isotretinoin. Isotretinoin induces apoptosis in sebocytes, leading to a decrease in sebum production. Isotretinoin also reduces the formation of comedones by reducing hyperkeratinization through an unknown mechanism. Isotretinoin does not directly kill bacteria but it does reduce the size of sebum ducts and makes the microenvironment less hospitable to acne causing bacteria. It may also increase immune mechanisms and alter chemotaxis of monocytes to reduce inflammation. There is preliminary evidence suggesting isotretinoin may interact with FoxO1, which may explain a substantial number of isotretinoin's unexplained actions.

This paper reviews the teratogenicity of isotretinoin in regard to aspects of species variation, toxicokinetics, and metabolism. The insensitive species (rat, mouse) eliminate the drug rapidly through detoxification to the beta-glucuronide; also, placental transfer is limited in these species. On the other hand, in sensitive species (primates), the drug is predominantly metabolized to the active 13-cis-4-oxo-retinoic acid; placental transfer is more extensive here. The beta-glucuronides showed limited placental transfer in all species examined; these metabolites exhibited very low, if any, measurable concentrations in the human. The 13-cis-retinoic acid is not appreciably bound to cellular retinoid-binding proteins or nuclear receptors and exhibits low tissue distribution and placental transfer. Its access to the nucleus may be extensive. Because of the long half life of 13-cis-retinoic acid, continuous isomerization results in significant area under the concentration-time curve levels of all-trans-retinoic acid in the mouse, monkey and the human; the all-trans-retinoic acid formed is extensively distributed across the placenta and may be an important factor that contributes to the teratogenic potency of 13-cis-retinoic acid. Isomerization cannot explain the teratogenic effects of 13-cis-retinoic acid in the rat and rabbit. It is concluded that the high teratogenic activity of isotretinoin in sensitive species (human, monkey) is related to slow elimination of the 13-cis-isomer, to metabolism to the 4-oxo-derivative, to increased placental transfer, to continuous isomerization and significant exposure of the target tissue to all-trans-retinoic acid; and to lack of binding to cytoplasmic retinoid binding proteins that could possibly result in ready access to the nucleus.

The half life ranges from 7-39 hours with a mean elimination half life of 20 hours. The half life of 4-oxo-13-cis-retinoic acid ranges from 17-50 hours with a mean elimination half life of 25 hours.

Following oral administration of an 80 mg dose of (14)C-isotretinoin as a liquid suspension, (14)C-activity in blood declined with a half-life of 90 hours.

After a single 80 mg oral dose of isotretinoin to 74 healthy adult subjects under fed conditions, the mean +/- SD elimination half-lives of isotretinoin and 4-oxo-isotretinoin were 21 +/- 8.2 hours and 24 +/- 5.3 hours, respectively.

Blood concentrations of isotretinoin decline in a biphasic manner. In adults with normal renal function, the half-life in the initial phase averages 0.5 hours and the half-life in the terminal phase averages 10-20 hours (range: 7-39 hours).

... Plasma concentration of isotretinoin following single and multiple doses peak between 2 to 4 hr and exhibit elimination half-lives of 10 to 20 hr ...

For more Biological Half-Life (Complete) data for 13-cis-Retinoic acid (6 total), please visit the HSDB record page.

Isotretinoin, or 13-cis-retinoic acid can undergo reversible cis-trans isomerization to all-trans-retinoic acid. Isotretinoin undergoes 4-hydroxylation to 4-hydroxy-13-cis-retinoic acid, which is oxidized to the main metabolite 4-oxo-13-cis-retinoic acid.. All-trans-retinoic acid undergoes 4-hydroxylation to 4-hydroxy-all-trans-retinoic acid, which is oxidized to 4-oxo-all-trans-retinoic acid. 4-oxo-13-cis-retinoic acid can undergo reversible cis-trans isomerization to 4-oxo-all-trans-retinoic acid.

... In human volunteers and patients, one major blood metabolite of isotretinoin is 4-oxo-isotretinoin which undergoes slower elimination than isotretinoin and may itself be a participant in teratogenesis.

This paper reviews the teratogenicity of isotretinoin in regard to aspects of species variation, toxicokinetics, and metabolism. The insensitive species (rat, mouse) eliminate the drug rapidly through detoxification to the beta-glucuronide; also, placental transfer is limited in these species. On the other hand, in sensitive species (primates), the drug is predominantly metabolized to the active 13-cis-4-oxo-retinoic acid; placental transfer is more extensive here. The beta-glucuronides showed limited placental transfer in all species examined; these metabolites exhibited very low, if any, measurable concentrations in the human. The 13-cis-retinoic acid is not appreciably bound to cellular retinoid-binding proteins or nuclear receptors and exhibits low tissue distribution and placental transfer. Its access to the nucleus may be extensive. Because of the long half life of 13-cis-retinoic acid, continuous isomerization results in significant area under the concentration-time curve levels of all-trans-retinoic acid in the mouse, monkey and the human; the all-trans-retinoic acid formed is extensively distributed across the placenta and may be an important factor that contributes to the teratogenic potency of 13-cis-retinoic acid. Isomerization cannot explain the teratogenic effects of 13-cis-retinoic acid in the rat and rabbit. It is concluded that the high teratogenic activity of isotretinoin in sensitive species (human, monkey) is related to slow elimination of the 13-cis-isomer, to metabolism to the 4-oxo-derivative, to increased placental transfer, to continuous isomerization and significant exposure of the target tissue to all-trans-retinoic acid; and to lack of binding to cytoplasmic retinoid binding proteins that could possibly result in ready access to the nucleus.

Isotretinoin is metabolized in the liver by the cytochrome P-450 (CYP) microsomal enzyme system, principally by CYP2C8, CYP2C9, CYP3A4, and CYP2B6 isoenzymes, to several metabolites (e.g., 4-oxo-isotretinoin, retinoic acid [tretinoin], and 4-oxo-retinoic acid [4-oxo-tretinoin]). Retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion, and the administration of one isomer will give rise to the other. Isotretinoin also is irreversibly oxidized to 4-oxo-isotretinoin, which forms its own geometric isomer, 4-oxo-tretinon. All of these metabolites possess retinoid activity that is more than that of the parent compound in some in vitro models. However, the clinical importance of these models is unknown. Concurrent administration of food has been shown to increase the extent of formation of all metabolites in plasma when compared to administration of isotretinoin under fasted conditions. In addition, the exposure of patients to 4-oxo-isotretinoin at steady-state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin.

In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4 and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces.

For more Metabolism/Metabolites (Complete) data for 13-cis-Retinoic acid (6 total), please visit the HSDB record page.

EH28UP18IF

ISOTRETINOIN

Established Pharmacologic Class [EPC] - Retinoid

Chemical Structure [CS] - Retinoids

Isotretinoin is a Retinoid.

ISOTRETINOIN

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

An agent that causes the production of physical defects in the developing embryo.

Patients reach a maximum concentration of 74-511ng/mL after 1-4 hours following a 100mg oral dose. Isotretinoin is better absorbed with a high fat meal and bioavailability may change from one brand to another. Following a 40mg oral dose, fasted subjects reached a maximum concentration of 314ng/mL in 2.9 hours with an area under the curve of 4055ng/mL\*hr. Subjects given a high fat meal and a 40mg oral doses reached a maximum concentration of 395ng/mL in 6.4 hours with an area under the curve of 6095ng/mL\*mL.

Isotretinoin and its metabolites are conjugated and excreted in the urine and feces in similar amounts. 53-74% of an oral dose is eliminated as unchanged isotretinoin in the feces.

The volume of distribution in humans is unknown because there is no intravenous preparation. In a study of pediatric patients with neuroblastoma the volume of distribution was found to be 85L. The volume of distribution was also found to be 2432mL/kg in guinea pigs and 1716mL/kg in obese rats.

The clearance of isotretinoin is 15.9L/h in pediatric patients with neuroblastoma. Clearance is also 21.3mL/min/kg in guinea pigs and 7.2mL/min/kg in obese rats.

Following oral administration of isotretinoin, there is an apparent lag time of about 0.5-2 hours before the drug appears in systemic circulation. The lag time is thought to result from disintegration of the capsule and subsequent dissolution of the drug in GI contents. Absorption of the drug after this lag time is rapid. The actual bioavailability of orally administered isotretinoin has not been determined in humans, but studies in animals indicate that about 25% of an oral dose of the drug reaches systemic circulation as unchanged isotretinoin The low bioavailability observed in animals may result from biodegradation of the drug in the GI lumen and/or metabolism of the drug during absorption (in the GI mucosa) and first pass through the liver. Food and/or milk increase GI absorption of isotretinoin. Peak blood isotretinoin concentrations are slightly delayed and substantially increased and the area under the blood concentration-time curve (AUC) of the drug is approximately 1.5-2 times greater when isotretinoin is administered 1 hour before, concomitantly with, or 1 hour after a meal than when the drug is administered in the fasting state. Because of its high lipophilicity, oral absorption of isotretinoin is enhanced when the drug is administered with a high-fat meal. In a crossover study of 74 healthy adults who received a single 80-mg isotretinoin dose (as two 40-mg capsules) under fasted and fed conditions, both the peak plasma concentration and total area under the plasma concentration-time curve (AUC) of the drug were more than doubled when isotretinoin was administered immediately after a standardized high-fat meal compared with administration in the fasted state. Because the observed elimination half-life of the drug remained unchanged, it is suggested that food appears to increase the bioavailability of isotretinoin without altering its disposition. The time to peak concentration was also increased with food and may be related to a longer absorption phase. Consequently, the manufacturers recommend that isotretinoin capsules always be administered with food.

The harmonic mean elimination for the simultaneous iv and oral administration of isotretinoin was approx 5.5 hr. The mean blood clearance, following iv admin, and the intrinsic clearance, following oral administration, were 5.19 and 6.63 mL/min/kg, respectively. The average abs bioavailability was approx 21% indicating an overall 1st-pass effect of approx 80%. Analysis of gut contents for total (14)-C activity suggested that a fraction of the isotretinoin dose was biologically or chemically degraded in the gut lumen prior to absorption.

Dermatologic Agents; Teratogens

MEDICATION

Use (kg; approx.) in Germany (2009): >250

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.