Azathioprine

Absorption

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

Toxicity

The oral LD50 in mice is 2500mg/kg and in rats is 400mg/kg.
Patients experiencing an overdose may present with bone marrow hypoplasia, bleeding, and infection, which may progress to death. Patients should be treated with supportive and symptomatic treatments. 8 hour hemodialysis may remove 45% of a dose from serum.

Chemical properties

Yellow Solid

Chemical properties

Azathioprine is a complex heterocyclic compound which forms pale yellow crystals.

Originator

Imuran,Wellcome,UK,1964

The Uses of Azathioprine

An immunosuppressive antimetabolite. Also active as disease modifying antirheumatic drug (DMARD). Azathioprine is a purine analog with immunosuppressive effects.

The Uses of Azathioprine

immunosuppressant, antineoplastic, antirheumatic

The Uses of Azathioprine

Azathioprine is an immunosuppressive purine antimetabolite. The mechanism of action of azathioprine is as a nucleic acid synthesis inhibitor. It has shown promise in treatment of alopecia areata (autoimmune hair loss), with no difference in effectiveness between genders.

Background

Azathioprine is a prodrug of 6-mercaptopurine, first synthesized in 1956 by Gertrude Elion, William Lange, and George Hitchings in an attempt to produce a derivative of 6-mercaptopurine with a better therapeutic index. Azathioprine is used to treat inflammatory conditions like rheumatoid arthritis and as an immunosuppressant in the prevention of renal transplant rejection.
Azathiprine was granted FDA approval on 20 March 1968.

Indications

Azathioprine is indicated to treat rheumatoid arthritis and prevent renal transplant rejection.

Definition

ChEBI: A thiopurine that is 6-mercaptopurine in which the mercapto hydrogen is replaced by a 1-methyl-4-nitroimidazol-5-yl group. It is a prodrug for mercaptopurine and is used as an immunosuppressant, prescribed for the treatment of inflammatory conditions and a ter organ transplantation and also for treatment of Crohn's didease and MS.

Indications

Azathioprine (Imuran) is a cytotoxic agent that preferentially destroys any rapidly dividing cell. Since immunologically competent cells are generally rapidly dividing cells, azathioprine is very effective as an immunosuppressive drug. Unfortunately, any cell that is replicating is a target for this action. This lack of specificity leads to serious side effects. Azathioprine, in combination with corticosteroids, has historically been used more widely than any other drug in immunosuppressive therapy. It is classified as a purine antimetabolite and is a derivative of 6-mercaptopurine.

Manufacturing Process

N,N'-Dimethyloxaldiamide is reacted with PCl5, to give 4-chloro-1-methyl imidazole. This is nitrated with HNO3 to give 5-nitro-1-methyl-4- chloroimidazole. Then, a mixture of 4.6 grams of anhydrous 6- mercaptopurine, 5 grams of 1-methyl-4-chloro-5-nitroimidazole and 2.5 grams of anhydrous sodium acetate in 100 ml of dry dimethyl sulfoxide was heated at 100°C for 7 hours.
After standing overnight at room temperature, the mixture was poured into 200 ml of cold water and the yellow precipitate of 6-(1'-methyl-4'-nitro-5'- imidazolyl)mercaptopurine (7.0 grams) collected. After recrystallization from 50% aqueous acetone, the product melted at 243-244°C, dec., and had an UV spectrum with λ maximum = 280 nm at pH 1 and λ max. = 285 nm at pH 11.

brand name

Imuran (Promethus).

Therapeutic Function

Immunosuppressive

General Description

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

Air & Water Reactions

Sensitive to oxidation in the air. Insoluble in water.

Reactivity Profile

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

Hazard

Confirmed carcinogen.

Fire Hazard

Flash point data for Azathioprine are not available. Azathioprine is probably combustible.

Contact allergens

This immunosuppressive and antineoplastic drug is derived from 6-mercaptopurine. It caused allergic contact dermatitis in a mother crushing tablets for her leukemic son, and occupational dermatitis in a pharmaceutical reconditioner of old tablet packaging machines, and in a production mechanic working in packaging for a pharmaceutical company.

Biochem/physiol Actions

Has shown promise in treatment of alopecia areata (autoimmune hair loss), with no difference in effectiveness between genders.

Mechanism of action

Azathioprine is a phase-specific drug that is toxic to cells during nucleic acid synthesis. Phase-specific drugs are toxic during a specific phase of the mitotic cycle, usually the S-phase, when DNA synthesis is occurring, as opposed to cycle-specific drugs that kill both cycling and intermitotic cells.
Azathioprine is converted in vivo to thioinosinic acid, which competitively inhibits the synthesis of inosinic acid, the precursor to adenylic acid and guanylic acid. In this way, azathioprine inhibits DNA synthesis and therefore suppresses lymphocyte proliferation.This effectively inhibits both humoral and cell-mediated immune responses.

Pharmacokinetics

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.

Pharmacology

Azathioprine is well absorbed following oral administration, with peak blood levels occurring within 1 to 2 hours. It is rapidly and extensively metabolized to 6- mercaptopurine, which is further converted in the liver and erythrocytes to a variety of metabolites, including 6- thiouric acid. Metabolites are excreted in the urine.The half-life of azathioprine and its metabolites in the blood is about 5 hours.

Clinical Use

Azathioprine is a relatively powerful antiinflammatory agent. Although its beneficial effect in various conditions is principally attributable to its direct immunosuppressive action, the antiinflammatory properties of the drug play an important role in its overall therapeutic effectiveness.
Azathioprine has been used widely in combination with corticosteroids to inhibit rejection of organ transplants, particularly kidney and liver allografts. However, it is usually reserved for patients who do not respond to cyclosporine plus corticosteroids alone.
Azathioprine also has applications in certain disorders with autoimmune components, most commonly rheumatoid arthritis. It is as effective as cyclophosphamide in the treatment of Wegener’s granulomatosis. It has largely been replaced by cyclosporine in immunosuppressive therapy. Relative to other cytotoxic agents, the better oral absorption of azathioprine is the reason for its more widespread clinical use.

Side Effects

The therapeutic use of azathioprine has been limited by the number and severity of adverse effects associated with its administration. Bone marrow suppression resulting in leukopenia, thrombocytopenia, or both may occur. GI toxicity may be a problem. It is also mildly hepatotoxic. Because of its immunosuppressive activity, azathioprine therapy can lead to serious infections. It has been shown to be mutagenic in animals and humans and carcinogenic in animals.

Safety Profile

Confirmed human carcinogen producing bladder tumors and leukemia. Poison by subcutaneous, intradermal, and intraperitoneal routes. Moderately toxic by ingestion. Human systemic effects: liver changes, hypermotility, diarrhea, nausea or vomiting, increased body temperature, BP lowering, decreased urine volume or anuria, normocytic anemia, bone marrow changes. An experimental teratogen. Other experimental reproductive effects. Human mutation data reported. When heated to decomposition it emits very toxic fumes of NO,xand SOx. An immunosuppressant.

Synthesis

Azathioprine, 6-[(1-methyl-4-nitroimidazol-5-yl)thio]purine (31.2.1), is synthesized by heteroarylation of the sulfhydrile group of 6-mercaptopurine (30.1.2.9) with 5-chloro-1-methyl-4-nitroimidazol in the presence of sodium acetate as a weak base.

Potential Exposure

Azathioprine is an immunosuppressive agent, generally used in combination with a corticosteroid to prevent rejection following renal homotransplantations. It also is used following transplantation of other organs. Other uses of azathioprine include the treatment of a variety of presumed autoimmune diseases, including rheumatoid arthritis; ankylosing spondylitis; systemic lupus erythematosus; dermatonyositis, periarteritis nodosa, scleroderma, refractory thombocytopenic purpura; autoimmune hemolytic anemia; chronic active liver disease; regional enteritis; ulcerative colitis; various autoimmune diseases of the eye; acute and chronic glomerulonephritis; the nephritic syndrome; Wegener’s granulomatosis; and multiple sclerosis.

Veterinary Drugs and Treatments

In veterinary medicine, azathioprine is used primarily as an immunosuppressive agent in the treatment of immune-mediated diseases in dogs. See Doses below for more information. For autoagglutinizing immune mediated hemolytic anemia, azathioprine is generally recommended to start at the time of diagnosis. When used in combination with cyclosporine, azathioprine has been used to prevent rejection of MHC-matched renal allografts in dogs.
Although the drug can be very toxic to bone marrow in cats, it is sometimes used to treat feline autoimmune skin diseases.

Drug interactions

Potentially hazardous interactions with other drugs
Allopurinol: enhances effect with increased toxicity. Reduce azathioprine dose by 50-75% if administered concomitantly - ideally avoid.
Antibacterials: increased risk of haematological toxicity with co-trimoxazole.
Anticoagulants: possibly reduced anticoagulant effect of coumarins.
Antipsychotics: avoid with clozapine.
Antivirals: myelosuppressive effects enhanced by ribavirin.
Ciclosporin: decreased ciclosporin absorption and bioavailability.
Cytotoxics may be additive or synergistic in producing toxicity, particularly on the bone marrow.
Febuxostat: avoid concomitant use.
Vaccines: risk of generalised infections with live vaccines - avoid.

First aid

If this chemical gets into the eyes, remove anycontact lenses at once and irrigate with water or normalsaline immediately for at least 20°30 min, occasionally lifting upper and lower lids. Seek medical attention immediately. If this chemical contacts the skin, removecontaminated clothing and wash immediately with soap andwater. Seek medical attention immediately. If this chemicalhas been inhaled, remove from exposure, begin rescuebreathing (using universal precautions, including resuscitation mask) if breathing has stopped and CPR if heart actionhas stopped. Transfer promptly to a medical facility. Whenthis chemical has been swallowed, get medical attention.Give large quantities of water and induce vomiting. Do notmake an unconscious person vomit.

Carcinogenicity

Azathioprine is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.

Metabolism

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.

Metabolism

Azathioprine is extensively metabolised to its active moiety mercaptopurine, which in turn is activated intracellularly by conversion to nucleotide derivatives. Mercaptopurine is rapidly and extensively metabolised in the liver, by methylation, oxidation and by the formation of inorganic sulfates. Thiol methylation is catalysed by the enzyme thiopurine methyltransferase (TPMT). TPMT activity is highly variable in patients because of a genetic polymorphism in the TPMT gene. About 10% of a dose of azathioprine is reported to be split between the sulfur and the purine ring to give 1-methyl-4-nitro-5-thioimidazole. The proportion of different metabolites is reported to vary between patients. Metabolites and small amounts of unchanged azathioprine and mercaptopurine are eliminated in the urine.

storage

Color Code—Blue: Health Hazard/Poison: Store ina secure poison location. Prior to working with this chemicalyou should be trained on its proper handling and storage.Store in a refrigerator under an inert atmosphere. A regulated, marked area should be established where this chemicalis handled, used, or stored in compliance with OSHAStandard 1910.1045.

Shipping

UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required.

Incompatibilities

Incompatible with reducing agents, such as hydrides (may cause the release of explosive gases), oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong acids (violent exothermic reaction), strong bases.