Azathioprine
Clinical data | |
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Pronunciation | /ˌæzəˈθaɪəˌpriːn/[1] |
Trade names | Azasan, Imuran, Jayempi, others |
Other names | AZA |
AHFS/Drugs.com | Monograph |
MedlinePlus | a682167 |
License data |
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By mouth, intravenous | |
ATC code | |
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Pharmacokinetic data | |
Bioavailability | 60±31% |
Protein binding | 20–30% |
Metabolism | Activated non-enzymatically, deactivated mainly by xanthine oxidase |
Elimination half-life | 26–80 minutes (azathioprine) 3–5 hours (drug plus metabolites) |
Excretion | Kidney, 98% as metabolites |
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JSmol) | |
Melting point | 238 to 245 °C (460 to 473 °F) |
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Azathioprine, sold under the brand name Imuran, among others, is an
Common side effects include
Azathioprine was first made in 1957.[9] It is on the World Health Organization's List of Essential Medicines.[10] In 2018, it was the 358th most commonly prescribed medication in the United States, with more than 800,000 prescriptions.[11]
Medical uses
Azathioprine is used alone or in combination with other immunosuppressive therapy to prevent rejection following organ transplantation, and to treat an array of
In the United States, it is approved by the Food and Drug Administration for use in kidney transplantation from human donors, and for rheumatoid arthritis.[14]
Transplantation
Azathioprine is used to prevent rejections of kidney or liver
Rheumatoid arthritis
Being a
Inflammatory bowel disease
Azathioprine has been used in the management of moderate to severe chronically active Crohn's disease,
Azathioprine treatment is associated with an increased risk of lymphoma, but if this is due to the drug or a predisposition related to Crohn's disease is unclear.[21] Lower doses of azathioprine are used as a therapy in children with refractory or corticosteroid-dependent Crohn's disease, without causing many side effects.[22] It may also be used to prevent flares in those with ulcerative colitis.[23]
Others
Azathioprine is sometimes used in systemic lupus erythematosus, requiring a maintenance dose of 15 mg or higher of prednisone in those who experience recurrent flares.[24]
It is used as an add-on therapy when steroid therapy is given by mouth for pemphigus and myasthenia gravis, as a "steroid-sparing" agent.[12][25][26] Azathioprine is also used to maintain remission in people who have granulomatosis with polyangiitis.[7]
It can be very effective in eczema and atopic dermatitis, though it is not commonly used.[12] The British National Eczema Society lists it as a third-line treatment for severe to moderate cases of these skin diseases.[27]
It was widely used for the treatment of multiple sclerosis until the first half of the 1990s. Concerns about increased risk of
A widely used therapy for idiopathic pulmonary fibrosis was azathioprine in combination with prednisone and N-acetylcysteine. A 2012 study showed that outcomes were worse with this combination than with placebo.[30]
Adverse effects
Nausea and vomiting are common adverse effects, especially at the beginning of a treatment. Such cases are met with taking azathioprine after meals or transient
It is listed by the
Pharmacogenetics
The enzyme
Cancers
Azathioprine is listed as a human carcinogen in the 12th Report on Carcinogens by the National Toxicology Program of U.S. Department of Health and Human Services, asserting that it is "known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans."[45] Since August 2009, the U.S. FDA has required warnings to be placed on packaging with respect to increased risks of certain cancers.[46]
The risks involved seem to be related both to the duration and the dosage used. People who have previously been treated with an
The various diseases requiring transplantation may in themselves increase the risks of
Cases of hepatosplenic T-cell lymphoma – a rare type of lymphoma – have been reported in patients treated with azathioprine. The majority occurred in patients with inflammatory bowel disease. Adolescents and young adult males were the majority of cases.[49] They presented with a very aggressive disease course, and with one exception, died of the lymphoma. The FDA has required changes to the labeling to inform users and clinicians of the issue.[50]
Skin cancers
In transplant patients,
Overdose
Large single doses are generally well tolerated; a patient who took 7.5 g azathioprine (150 tablets) at once showed no relevant symptoms apart from vomiting, slightly decreased white blood cell count, and marginal changes in liver function parameters. Main symptoms of long-term overdosing are infections of unclear origin, mouth ulcers, and spontaneous bleeding, all of which are consequences of its bone-marrow suppression.[31]
Interactions
Other purine analogues, such as allopurinol, inhibit xanthine oxidase, the enzyme that breaks down azathioprine, thus increasing the toxicity of azathioprine.[53] Low doses of allopurinol, though, have been shown to safely enhance the efficacy of azathioprine, especially in inflammatory bowel disease nonresponders.[54][55][56] This may still lead to lower lymphocyte counts and higher rates of infection, therefore the combination requires careful monitoring.[57][58]
Azathioprine decreases the effects of the
Pregnancy and breastfeeding
Azathioprine can cause birth defects.
Traditionally, as for all
Pharmacology
Pharmacokinetics
Azathioprine is absorbed from the gut to about 88%.
Azathioprine is a
Mechanism of action
Azathioprine inhibits purine synthesis. Purines are needed to produce DNA and RNA. By inhibiting purine synthesis, less DNA and RNA are produced for the synthesis of white blood cells, thus causing immunosuppression.
This section may be too technical for most readers to understand.(December 2014) |
Azathioprine is converted within tissues to 6-MP, some of which is converted, in turn, to
- The nucleotides are incorporated into newly synthesized (but nonfunctional) DNA, halting replication.
- The nucleotides act to inhibit glutamine-purine biosynthesis, one of the earlier steps in the synthesis of DNA and RNA. They achieve GPAT inhibition through a form of negative feedback called product inhibition.[71] Because actively replicating cells (such as cancer cells and the T cells and B cells of the immune system) are most active in synthesizing purine, making new DNA, these cells are most strongly affected.[72][12]
- A portion of the nucleotides is additionally phosphorylated to the triphosphate forms. These bind to
Chemistry
Azathioprine is a
Azathioprine is synthesized from 5-chloro-1-methyl-4-nitro-1H-imidazole and 6-mercaptopurine in
History
Azathioprine was synthesized by
Robert Schwartz investigated the effect of 6-MP on the immune response in 1958 and discovered that it profoundly suppresses the formation of
In April 1962, with regimens consisting of azathioprine and prednisone, the transplantation of kidneys to unrelated recipients (allotransplantation) was successful for the first time.[12][80] For many years, this kind of dual therapy with azathioprine and glucocorticoids was the standard antirejection regimen, until ciclosporin was introduced into clinical practice (by Calne as well) in 1978.
References
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- ^ "Label: Imuran - azathioprine tablet". Archived from the original on 20 October 2014. Retrieved 19 October 2014.
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- ^ National Toxicology Program (10 June 2011). "Report On Carcinogens – Twelfth Edition – 2011". National Toxicology Program. Archived (PDF) from the original on 16 July 2012. Retrieved June 20, 2012.
- ^ "FDA: Cancer Warnings Required for TNF Blockers". FDA. August 4, 2009. Archived from the original on July 3, 2012. Retrieved June 20, 2012.
- ^ International Agency for Research on Cancer (IARC) (1981). "Azathioprine – 5. Summary of Data Reported and Evaluation". Summaries & Evaluations. 26: 47. Archived from the original on 2006-09-06.
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- ^ "Imuran (azathioprine) Tablets and Injection". FDA. May 2011. Archived from the original on March 2, 2012. Retrieved June 20, 2012.
- ^ "Skin cancer alert for organ drug". BBC Online. BBC News. September 15, 2005. Archived from the original on October 14, 2012. Retrieved June 10, 2012.
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- ^ "Azathioprine Pathway". Small Molecule Pathway Database. Archived from the original on 2 July 2012. Retrieved 31 August 2012.
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Further reading
- Dean L (2012). "Azathioprine Therapy and TPMT Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. PMID 28520349. Bookshelf ID: NBK100661.