アザチオプリン

Pharmaceuticals

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Used in Switzerland

log Kow = 0.10

0.7

0.89

less than 1 mg/mL at 73 °F (NTP, 1992)

Insoluble

Very slightly soluble in ethanol and chloroform; sparingly soluble in dilute mineral acids; soluble in dilute alkali solutions

Insoluble in water

1.07e+00 g/L

>41.6 [ug/mL] (The mean of the results at pH 7.4)

Breast Feeding; Lactation; Milk, Human; Immunosuppressive Agents

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

Pharmaceuticals

Disease-modifying anti-rheumatic drugs (DMARDs)

469 to 471 °F (decomposes) (NTP, 1992)

dec 243-244 °C

243.5 °C

Azathioprine appears as pale yellow crystals or yellowish powder. Decomposes at 243-244 °C. Used for the treatment of rheumatoid arthritis. A known carcinogen.

Solid

Azathioprine... is stated to be stable in neutral or acid solns but is hydrolyzed to mercaptopurine in alkaline solns, expecially on warming. Max stability occurs at pH 5.5-6.5. Hydrolysis to mercaptopurine also occurs in the presence of sulfhydryl compounds such as cysteine. /Azathioprine sodium/

7.87 (at 25 °C)

pKa = 8.2

172.4 Ų [M+Na]+ [CCS Type: DT; Buffer gas: N2; Ionization: ESI+; Dataset: TOXCAST; Source Identifier: DTXSID4020119]

155.1 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Danger

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

P203, P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P318, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 107 reports by companies from 10 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

H302: Harmful if swallowed [Warning Acute toxicity, oral]

Hazard Traits - Carcinogenicity; Developmental Toxicity

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

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

/A review of literature/ to assess the short-term effects of azathioprine for the treatment of rheumatoid arthritis.[Suarez-Almazor ME et al; Cochrane Database Sysy Rev 4: CD001461 (2001)]

National Toxicology Program. Eleventh Report on Carcinogens (2005). The Report on Carcinogens is an informational scientific and public health document that identifies and discusses substances (including agents, mixtures, or exposure circumstances) that may pose a carcinogenic hazard to human health. Azathioprine (446-86-6) is listed as known to be a human carcinogen.[Available from, as of July 31, 2009: http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s018azat.pdf]

AZATHIOPRINE may react exothermically with acids. Incompatible with isocyanates, peroxides, phenols, epoxides, anhydrides, and acid halides. Hydrolyzed by strongly basic solutions (NTP, 1992). May react with strong reducing agents to generate flammable gaseous hydrogen or hydrogen sulfide.

Acute Tox. 4 (100%)

Acute toxicity (Oral) - Category 4

PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped & will resist attack from the carcinogen. Both bottle & the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies & airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary & secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen & is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container & the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest & most secure form of transport & notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/

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.

Storage of the constituted soln in the original vial and in plastic syringes (Jelco) at 20-25 °C under fluorescent light resulted in no decomp or precipitation in 16 days. At 4 °C in the dark, a visible precipitate formed after four days. /Azathioprine sodium/

Azathioprine sodium 100 mg/50 ml diluted in dextrose 5% in water, sodium chloride 0.9%, or sodium chloride 0.45% in PVC bags was stored at 20-25 °C under fluorescent light and at 4 °C in the dark. No decomp occurred in the solns over 16 days of storage. However, a precipitate formed in the dextrose 5% in water admixtures by the 16th day. No precipiatate was observed after 8 days of storage. /Azathioprine sodium/

PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen & date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/

In the event of spills or leaks, the manufacturer recommends the use of sodium hypochlorite 5% (household bleach) and sodium hydroxide (concn unspecified) to inactivate azathioprine. /Azathioprine sodium/

PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/

SMALL SPILLS AND LEAKAGE: If you spill this chemical, dampen the solid spill material with 5% ammonium hydroxide, then transfer the dampened material to a suitable container. Use absorbent paper dampened with 5% ammonium hydroxide to pick up any remaining material. Your contaminated clothing and the absorbent paper should be sealed in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with 5% ammonium hydroxide 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.

PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds & specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods & recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp & carcinogenic wastes generated by this treatment conducted to & burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter & misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols & thiosulfate. The reactivity of various alkylating agents varies greatly ... & is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness & safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food & beverage containers or utensils, & the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, & rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes & wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth & purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care & vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... & when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, & contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) & label fixed to it, giving date of test & avg air-flow measured. This test should be repeated periodically & after any structural changes. /Chemical Carcinogens/

For more Preventive Measures (Complete) data for AZATHIOPRINE (9 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 a combination filter cartridge, i.e. organic vapor/acid gas/HEPA (specific for organic vapors, HCl, acid gas, SO2 and a high efficiency particulate filter). (NTP, 1992)

PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/

Xanthine oxidase, an enzyme of major importance in the catabolism of metabolites of azathioprine, is blocked by allopurinol. If azathioprine and allopurinol are used in the same patient, the azathioprine dose must be decreased to 25 to 33% of the usual dose, but it is best not to use these two drugs together. Adverse effects resulting from coadministration of azathioprine with other myelosuppressive agents or ACE inhibitors include leukopenia, thrombocytopenia, and/or anemia ...

Allopurinol inhibits the principal metabolic pathway of azathioprine, the oxidative metabolism of mercaptopurine by xanthine oxidase. This may lead to toxic accumulation of azathioprine with concomitant bone marrow depression.

Therapeutic use may lead to bone marrow depression, hepatic dysfunction infection, drug fever, rash, urticarial eruption, hypersensitivity vasculitis, nausea, vomiting, and diarrhea, and possibly an increase in non-Hodgkin's lymphoma when used with corticosteroids in rheumatoid arthritis.

Allopurinol-induced inhibition of xanthine oxidase-mediated metabolism may result in greatly increased azathioprine activity and toxicity; concurrent use should be avoided if possible, especially in renal transplant patients, because of the high risk of 6-mercaptopurine (azathioprine metabolite) accumulation and consequent azathioprine toxicity if the transplanted kidney is rejected; if concurrent use is essential, it is recommended that azathioprine dosage be reduced to one quarter to one third of the usual dosage, the patient be carefully monitored, and subsequent dosage adjustments be based on patient response and evidence of toxicity.

For more Interactions (Complete) data for AZATHIOPRINE (8 total), please visit the HSDB record page.

Azathioprine has been associated with several forms of hepatotoxicity, including mild, transient and asymptomatic rises in serum aminotransferase levels, an acute cholestatic injury developing during the first year of starting therapy, and a chronic hepatic injury marked by peliosis hepatis, veno-occlusive disease or nodular regenerative hyperplasia that typically arises 1 to 5 years after starting azathioprine.

Skin Sensitizer - An agent that can induce an allergic reaction in the skin.

Complications occur in 15 to 28% of patients.

IDENTIFICATION: Group: Other Immunosuppressive agents. Azathioprine: pale yellow, odorless powder. The drug is insoluble in water and very slightly soluble in ethanol. HUMAN EXPOSURE: Summary: Main risks and target organs: Azathioprine is a myelotoxic and hepatotoxic immunosuppressive agent. Bone marrow and liver are the main targets but gastrointestinal tract, kidney, lungs, CNS and skin may also be affected. Transient gastroenteritis may be observed with massive overdose. Leukopenia is the main toxic effect which may occur during azathioprine therapy and in the overdose patient. Liver and kidney function tests may be altered but usually returned to normal after discontinuation of the drug. Summary of clinical effects: Oral ulceration occurs rarely with therapeutic doses but may be seen with large doses. Gastrointestinal disturbances such as nausea, vomiting, abdominal pain and diarrhea can appear mainly at higher doses. Acute pancreatitis was also reported following long term azathioprine treatment. Suppression of the bone marrow mainly leukopenia and occasionally pancytopenia may be seen after therapeutic doses and overdoses of azathioprine. Septic shock due to this immunosuppression may occur. Hepatic dysfunction (hepatocellular and cholestatic), venocclusive disease and hemangioma of the liver following azathioprine therapy were documented. Acute restrictive lung disease, interstitial nephritis and a case of progressive leukoencephalopathy after 4 years azathioprine therapy were reported. Skin rash, alopecia and urticaria and a case of palmar-plantar erythema with desquamation and pain were also documented. Diagnosis: Diagnosis of azathioprine overdose is based on history of the drug taken and clinical findings mainly gastrointestinal dysfunction, leukopenia and liver dysfunction. Peripheral cell blood counts and liver function tests are required. Estimation of 6-thioguanine nucleotide, a cytotoxic metabolite of azathioprine in red blood cell may confirm the diagnosis and could also be used to predict bone marrow toxicity of azathioprine. Indications: Uses: Azathioprine is used as an adjunct for the prevention of the rejection of kidney allografts. The drug is used in conjunction with other immunosuppressive therapy including local radiation therapy, corticosteroids, and other cytotoxic agents. Azathioprine may be used for the treatment of conditions which involve derangement of the immune system including chronic active hepatitis, severe rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, pemphigus vulgaris, polyarteritis nodosa, acquired hemolytic anemia, Crohn's disease and idiopathic thrombocytopenia. Contraindications: Azathioprine is contraindicated in patients who are hypersensitive to the drug. Azathioprine is also contraindicated in those patients with renal failure, impaired hepatic function and in pregnant women. Routes of entry: Oral: Azathioprine is usually administered orally. Parenteral: Following renal transplantation, azathioprine may initially be given intravenously to patients unable to tolerate oral medication. Oral therapy should replace parenteral therapy as soon as possible. Kinetics: Absorption by route of exposure: Azathioprine is readily absorbed from the gastrointestinal tract with only 12.6% of the dose being detected in the stool over a 48 hour period. Distribution by route of exposure: Azathioprine is rapidly distributed throughout the body with peak plasma concentrations being reached at 1 to 2 hours after dosing. Small amounts of azathioprine bind to plasma proteins (to a maximum of 30%) and only very small amounts enter the brain. Azathioprine crosses the placenta and trace amounts of the 6-mercaptopurine metabolite have been detected in fetal blood. Biological half-life by route of exposure: The plasma half-life of azathioprine is 3 to 5 hours. Metabolism: Azathioprine is metabolized in vivo to mercaptopurine, apparently by sulfhydryl compounds such as glutathione. Mercaptopurine is oxidized and methylated to several derivatives among which 6-thiouric acid predominates; the proportion of metabolites varies amongst individuals. The fate of the nitromethylimidazole portion of azathioprine has not been completely elucidated. Small amounts of azathioprine are also split to give 1-methyl-4-nitro-5-thioimidazole. The active metabolites, 6-thioguanine nucleotides, responsible for the therapeutic action, are formed intracellularly and appear to have very long half-lives. Elimination by route of exposure: The metabolites of azathioprine are excreted by the kidneys; only small amounts of azathioprine and mercaptopurine are excreted intact. In the 24 hour period after administration up to 50% of the dose is excreted in the urine with 10% as the parent drug. There is no data concerning azathioprine excretion in breast milk. Pharmacology and toxicology: Mode of action: Toxicodynamics: The principal toxic effect of azathioprine is bone marrow depression manifested by leukopenia, macrocytic anemia, pancytopenia, and thrombocytopenia, which may result in prolongation of clotting time and eventual hemorrhage. Pharmacodynamics: The exact mechanism of immunosuppressive activity of azathioprine has not been determined. Azathioprine which is an antagonist to purine metabolism may inhibit RNA and DNA synthesis. The drug may also be incorporated into nucleic acids resulting in chromosome breaks, malfunctioning of the nucleic acids, or synthesis of fraudulent proteins. The drug may also inhibit coenzyme formation and functioning, thereby interfering with cellular metabolism. Mitosis may be inhibited by the drug. In patients who undergo renal transplantation, azathioprine suppresses hypersensitivities of the cell-mediated type and causes variable alterations in antibody production. Human data: Adults: Severe pancytopenia has been observed in about 1% of the patients. Children: Lymphopenia, decreased IgG and IgM concentrations, cytomegalovirus infection. Cytogenetic damage was observed in human lymphocytes in vitro. Acute myelogenous leukemia and solid tumours have occurred in patients with rheumatoid arthritis who received the drug. Mutagenicity: Azathioprine is mutagenic in animals and humans, chromosomal abnormalities have been documented in humans receiving azathioprine, but the abnormalities were reversed following discontinuance of the drug. Interactions: Azathioprine dose should be reduced 75% when administered with allopurinol, as allopurinol affects the metabolism of mercaptopurine, a metabolite of azathioprine. Azathioprine may reduce the effect of certain neuromuscular blocking agents including curare and related non-depolarizing drugs. Certain cytotoxic agents may be additive or synergistic in producing toxicity when used in conjunction with azathioprine. The Committee on Safety of Medicines have advised that azathioprine and penicillamine should not be used concurrently. The effects of azathioprine and corticosteroids could be synergistic. Azathioprine may reduce the anticoagulant effect of warfarin. ANIMAL/PLANT STUDIES: Studies with animals have shown that the haemopoietic system is affected by azathioprine with depression of granulopoiesis, megakaryocytes and, hence, platelet formation. Reversible hepatoxicity has been observed in dogs. Various teratogenic effects have been observed in rabbits, showing skeletal abnormalities. In mice embryolethalite was observed. Carcinogenicity: Azathioprine is carcinogenic in animals. Teratogenicity: Azathioprine is teratogenic in rabbits and mice when given in dosages equivalent to the human dosage. Abnormalities included skeletal malformations and visceral anomalies. Mutagenicity: Azathioprine is mutagenic in the Ames test.

Toxicity symptoms include gastrointestinal symptoms, bradycardia, hepatotoxicity, myelosuppression. Acute toxicity usually happens when more than 1.5 times of daily dose is taken by the patient.

Azathioprine antagonizes purine metabolism and may inhibit synthesis of DNA, RNA, and proteins. It may also interfere with cellular metabolism and inhibit mitosis. Its mechanism of action is likely due to incorporation of thiopurine analogues into the DNA structure, causing chain termination and cytotoxicity.

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=446-86-6]

PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/

/HUMAN EXPOSURE STUDIES/ Azathioprine ...may be associated with an increased risk of development of carcinomas in humans, especially skin cancer and reticulum cell tumors or lymphomas in renal transplant patients and acute myelocytic leukemia and some solid tumors in rheumatoid arthritis patients. The risk of neoplastic toxicity appears to be lower in rheumatoid arthritis patients than in renal transplant patients; however, there is evidence that the risk is increased with prior use of alkylating agents.

/HUMAN EXPOSURE STUDIES/ Azathioprine is the most common drug in the U.S. implicated in causing /(veno-occlusive disease)/ VOD. Approx 20% of bone marrow and renal transplant patients may be affected with a mortality rate of 50%. VOD results from a nonthrombotic concentric occlusion of the lumen of small intrahepatic veins, also known as "bush tea" disease. /from table/

/SIGNS AND SYMPTOMS/ The most common adverse effect of azathioprine is bone marrow suppression that presents as leukopenia or, less frequently, thrombocytopenia, and megaloblastic anemia. Myelosuppression is dose-dependent and typically observed after 7-14 days of therapy ... . Bone marrow suppression may be related to a genetic deficiency of the enzyme, thiopurine methyl transferase (TPMT) deficiency. Low activity of this enzyme is rare but does lead to greater availability of 6-mercaptopurine, elevated 6-thioguanine levels, and susceptibility to myelosuppression. Low levels of TPMT have been associated in some transplant patients with azathioprine at the time of severe myelotoxicity.

Azathioprine

Group 1: Carcinogenic to humans

Volume 26: (1981) Some Antineoplastic and Immunosuppressive Agents

2012

2008

1, carcinogenic to humans. (L135)

Drug Induced Liver Injury Rank (DILIrank 2.0)

Azathioprine

vMost-DILI-concern

5

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Acute Exposure/ Treatment of mice with even low doses of azathioprine was found to incr cell cycle time of promonocytes by over 5 hr and led to a 70% reduction of monocyte production.

/LABORATORY ANIMALS: Acute Exposure/ Of 60 newborn, random-bred Swiss mice of both sexes, 22 survived day 30 after ip administration of 40 mg/kg body weight azathioprine (dissolved in 0.1N NaOH and diluted in physiological saline) once a day on days 1-4 after birth. The experiment was terminated after 180-200 days. Of 135 controls treated with identical amounts of physiological saline, 124 survived day 30. Leukemia developed in 4/20 treated mice (20%), and in only 1 of 119 controls. This difference was reported to be statistically significant (p < 0.001). Azathioprine was administered under identical conditions to an additional group of 17 newborn mice as 4 single doses of 10 mg/kg on days 1-4 after birth. In the 14 animals that survived day 30, no leukemia occurred; 2 (14%) animals developed lung adenomas, and this type of tumor was reported in 10/119 (8%) controls.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Azathioprine was administered intramuscularly into the thigh muscles of male inbred NZB mice before onset of autoimmune hemolytic anemia, which develops spontaneously in mice of this strain. Azathioprine was dissolved in 0.1N NaOH and then diluted with physiological saline to a final concentration of 10 mg/ml azathiopine; single doses corresponded to 100 mg/kg body weight. The 16 mice, aged 2 months, were matched into two similar groups on the basis of body weight and hematocrit readings; 8 mice were injected 3 times a week for 4 weeks, followed by 2 injections during the 5th week and then one injection a week, for a total treatment period of 6 months; 8 controls were given the solvent only. Of the treated mice, 6/8 (75%) had malignant thymic lymphomas; 4 of these died during treatment, and in the other 2 animals the tumors were diagnosed after termination of the experiment. No lymphoma was seen in the 6 control mice examined histologically at the end of the study.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Two groups, each of 25 male and 25 female outbred Swiss-Webster-derived mice, 6 weeks old, were given ip injections of either 7.5 or 15 (females, 30) mg/kg body weight azathioprine as an NaOH-stabilized solution in physiological saline 3 times a week for 6 months. Animals that survived over 100 days were observed for up to 12 further months, at which time they were killed. Controls consisted of 254 untreated mice. The survival times of the treated animals were reported as percentages of that of the controls (no precise definition of the mode of calculation was given): the survival times of treated male mice were reported to be 51-77% that of untreated controls, and the corresponding figures for females were 23-75%. Animals that died before day 100 on test were excluded from evaluation. The incidence of 9/21 (43%) tumor-bearing males and of 25/40 (63%) tumor-bearing females was 1.5-2 times higher than that in controls (26%), in which there was only a small difference between males (28/101) and females (38/153). Histologically, 4 lymphasarcomas and 5 lung and 2 uterine tumors in females.

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

Classification of carcinogenicity: 1) evidence in humans: sufficient; 2) evidence in animals: limited. Overall summary evaluation of carcinogenic risk to humans is Group 1: The agent is carcinogenic to humans. /From table/

Azathioprine: known to be a human carcinogen.

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

L04AX01

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

L04AX01

Azathioprine is an immunosuppressive agent which functions through modulation of rac1 to induce T cell apoptosis, as well as other unknown immunosuppressive functions. It has a long duration of action as it is given daily, and has a narrow therapeutic index. Patients should be counselled regarding the risk of malignancies of the skin and lymphomas.

Azathioprine's mechanism of action is not entirely understood but it may be related to inhibition of purine synthesis, along with inhibition of B and T cells. 6-thioguanine triphosphate, a metabolite of azathioprine, modulates activation of rac1 when costimulated with CD28, inducing T cell apoptosis. This may be mediated through rac1's action on mitogen-activated protein kinase, NF-kappaB.

Following exposure to nucleophiles ... azathioprine is cleaved to 6-mercaptopurine which, in turn, is converted to additional metabolites that inhibit de novo purine synthesis. 6-Thio-IMP, a fraudulent nucleotide, is converted to 6-thio-GMP and finally to 6-thio-GTP, which is incorporated into DNA and gene translation is inhibited. Cell proliferation is prevented, inhibiting a variety of lymphocyte functions.

Azathioprine (AZA), one of the antimetabolite drugs, is a purine analog that is more potent than the prototype 6-mercaptopurine, as an inhibitor of cell replication. Immunosuppression likely occurs because of the ability of the drug to inhibit purine biosynthesis. ... Although T-cell functions are the primary targets for this drug, inhibition of /(natural killer cells)/ NK function and macrophage activities has also been reported.

Azathioprine inhibits DNA synthesis and, as a purine antimetabolite, exerts its effect on activated lymphocytes, which requires purines during their proliferative phase. It inhibits both cellular and humoral responses, but does not interfere with phagocytosis or interferon production. It is a nonspecific cytotoxic agent. Its immunosuppressive effect is believed to be due to mercaptopurine, to which it is metabolized.

The exact mechanism of immunosuppressive action is unknown since the exact mechanism of the immune response itself is complex and not completely understood. The immunosuppressive effects of azathioprine involve a greater suppression of delayed hypersensitivity and cellular cytotoxicity tests than of antibody responses. Azathioprine antagonizes purine metabolism and may inhibit synthesis of DNA, RNA, and proteins; it may also interfere with cellular metabolism and inhibit mitosis.

For more Mechanism of Action (Complete) data for AZATHIOPRINE (6 total), please visit the HSDB record page.

The half life of azathioprine is approximately 5 hours.

The elimination half-life of azathioprine is approximately 12 to 15 minutes, and that of 6-mercaptopurine is approximately 30 minutes to 4 hours. The total boby clearance of azathioprine is 60 ml/min/kg, and that of 6-mercaptopurine, 10 ml/min/kg.

The half-life of azathioprine itself is about 10 minutes, and that for mercaptopurine is about an hour.

Azathioprine is converted to 6-mercaptopurine nonenzymatically. 6-mercaptopurine is then metabolized to 6-methylmercaptopurine by thiopurine methyltransferase, 6-thiouric acid by xanthine oxidase, or 6-thiosine-5'-monophosphate by hypoxanthine phosphoribosyltransferase. 6-thiosine-5'-monophosphate is metabolized to 6-methylthiosine-5'-monophosphate by thiopurine methyltransferase or 6-thioxanthylic acid by inosine monophosphate dehydrogenase. 6-thioxanthylic acid is metabolized by guanosine monophosphate synthetase to 6-thioguanine monophosphate, the first of the 6-thioguanine nucleotides. 6-thioguanine monophosphate is phosphorylated to produce the remaining 6-thioguanine nucleotides, 6-thioguanine diphosphate and 6-thioguanine triphosphate.

Orally administered azathioprine is rapidly divided in vivo to form 6-mercaptopurine.

Metabolized in vivo to 6-mercaptopurine, q.v.

Azathioprine is metabolized to 6-mercaptopurine.

Primarily converted to the active metabolites 6-mercaptopurine and 6-thioinosinic acid via a non-enzymatica process and glutathione transferases. Activation of 6-mercaptopurine occurs via hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and a series of multi-enzymatic processes involving kinases to form 6-thioguanine nucleotides (6-TGNs) as major metabolites Route of Elimination: Both compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver; no azathioprine or mercaptopurine is detectable in urine after 8 hours.

MRK240IY2L

AZATHIOPRINE

Mechanisms of Action [MoA] - Nucleic Acid Synthesis Inhibitors

Chemical Structure [CS] - Nucleosides

Established Pharmacologic Class [EPC] - Purine Antimetabolite

Chemical Structure [CS] - Purines

Drugs that are chemically similar to naturally occurring metabolites, but differ enough to interfere with normal metabolic pathways. (From AMA Drug Evaluations Annual, 1994, p2033)

Antimetabolites that are useful in cancer chemotherapy.

Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-CELLS or by inhibiting the activation of HELPER CELLS. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of INTERLEUKINS and other CYTOKINES are emerging.

Drugs that are used to treat RHEUMATOID ARTHRITIS.

Oral azathioprine is well absorbed, with a Tmax of 1-2h. Further data regarding the absorption of azathioprine is not readily available.

Azathioprine and mercaptopurine are not detectable in urine after 8 hours. Further data regarding the route of elimination of azathioprine are not available.

Data regarding the volume of distribution of azathioprine is not readily available.

Data regarding the clearance of azathioprine is not readily available.

Azathioprine and mercaptopurine are moderately bound to plasma proteins and are partially dialyzable. They are rapidly removed from the blood by oxidation or methylation in the liver and/or erythrocytes. Renal clearance is of little impact in biological effectiveness or toxicity, but dose reduction is practiced in patients with renal failure.

Azathioprine is well absorbed orally and reaches maximum blood levels within 1 to 2 hours after administration.

Used as an immunosuppressant and anticancer drug; [Kanerva, p. 1753]

MEDICATION

Use (kg; approx.) in Germany (2009): >2500

Azathioprine is used alone or in combination with other immunosuppressive therapy to prevent rejection following organ transplantation, and to treat an array of autoimmune diseases, including rheumatoid arthritis, pemphigus, systemic lupus erythematosus, Behcet's disease and other forms of vasculitis, autoimmune hepatitis, atopic dermatitis, myasthenia gravis, neuromyelitis optica (Devic's disease), restrictive lung disease, and others. It is also an important therapy and steroid-sparing agent for inflammatory bowel disease (such as Crohn's disease and ulcerative colitis) and for multiple sclerosis. In the United States it is currently approved by the Food and Drug Administration (FDA) for use in kidney transplantation from human donors, and for rheumatoid arthritis. Other uses are off-label. (Wikipedia)