Azathioprine

Azathioprine

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Systematic (IUPAC) name
6-[(1-methyl-4-nitro-1H-imidazol-5-yl)sulfanyl]-7H-purine
Clinical data
Pregnancy category	D
Routes of administration	oral
Legal status
Legal status	℞ (Prescription only)
Pharmacokinetic data
Bioavailability	Well absorbed
Metabolism	By xanthine oxidase
Biological half-life	3 hours
Excretion	Renal, minimally
Identifiers
CAS Number	446-86-6
ATC code	L04AX01 (WHO)
PubChem	CID 2265
DrugBank	APRD00811
ChemSpider	2178
Chemical data
Formula	C9H7N7O2S
Molar mass	277.263 g/mol[[]]
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Azathioprine (/ˌæzəˈθaɪɵpriːn/) is a drug that suppresses the immune system.

Azathioprine is used in organ transplantation and autoimmune disease. Some of the autoimmune diseases are rheumatoid arthritis, pemphigus, Inflammatory Bowel Disease (such as Crohn's disease and Ulcerative Colitis), multiple sclerosis, autoimmune hepatitis, atopic dermatitis, Myasthenia Gravis and restrictive lung disease.

Azathioprine interferes with the synthesis of purines (adenine and guanine), which is required for DNA synthesis. Fast-growing cells, including T-cells and B-cells, are particularly affected by the inhibition of purine synthesis.

It is a pro-drug, converted in the body to the active metabolites 6-mercaptopurine (6-MP) and 6-thioinosinic acid.

Azathioprine is produced by a number of generic manufacturers and as branded names (Azasan by Salix in the U.S., Imuran by GlaxoSmithKline in Canada and the U.S., Australia and UK, Azamun in Finland and Imurel in Scandinavia and France).

History

Azathioprine was first introduced into clinical practice by Sir Roy Calne, the British pioneer in transplantation. Following the work done by Sir Peter Medawar in discovering the immunological basis of rejection of transplanted tissues and organs, Calne introduced 6-mercaptopurine as an experimental immunosuppressant for kidney transplants cardiac transplantation. When azathioprine was discovered, he then introduced it as a less toxic replacement for 6-mercaptopurine. For many years, dual therapy with azathioprine and steroids was the standard anti-rejection regime, until cyclosporine was introduced into clinical practice (also by Calne) in 1978.

Mechanism of action

Azathioprine is a DNA synthesis inhibitor, as it is converted to a purine analogue inhibiting the proliferation of cells, especially lymphocytes. It is an effective drug used alone in certain autoimmune diseases, or in combination with other immunosuppressants in organ transplantation.

Immediate or short-term side-effects

Side-effects are uncommon, but include nausea, fatigue, hair loss, and rash. Because azathioprine suppresses the bone marrow, patients will be more susceptible to infection. Caution should be exercised when it is used in conjunction with purine analogues such as allopurinol. The enzyme thiopurine S-methyltransferase (TPMT) deactivates 6-mercaptopurine. Genetic polymorphisms of TPMT can lead to excessive drug toxicity, thus assay of serum TPMT may be useful to prevent this complication.

Despite being 15 times more expensive, Mycophenolate mofetil is increasingly being used in place of azathioprine in organ transplantation, as it is associated with less bone marrow suppression, fewer opportunistic infections, and a lower incidence of acute rejection. However azathioprine certainly still has a major role.

Long-term side-effects

File:AZA metabolism.jpg

Metabolic pathway for azathioprine

It is listed as a human carcinogen in the 11th Report on Carcinogens of the U.S. Department of Health and Human Services, although they note that the International Agency for Research on Cancer (IARC) considered some of the animal studies to be inconclusive because of limitations in the study design and inadequate reporting. The risks involved seem to be related both to the duration and to the dosage used. People that have previously been treated with an alkylating agent may have an excessive risk of cancers if treated with azathioprine. Epidemiological studies have provided "sufficient" evidence of Azathioprine carcinogenicity in humans, although the methodology of past studies and the possible underlying mechanisms are questioned. The various diseases requiring transplantation, and thus azathioprine, may in themselves increase the risks of non-Hodgkin's lymphoma, squamous cell carcinomas of the skin, hepatobiliary carcinomas and mesenchymal tumours to which azathioprine may add additional risks. Those receiving azathioprine for rheumatoid arthritis may have a lesser risk than those following transplantation.

Azathioprine is not thought to cause fetal malformation (teratogenesis) and any risk to the offspring of treated women is small. A more recent product monograph produced by Glaxo Smith Kline and dated June 2005 does note that IMURAN can cause fetal harm when given to a pregnant woman. Their document also states that the drug should not be given during pregnancy or in patients of reproductive potential without careful weighing of benefit versus the risks, and should be avoided whenever possible in pregnant women. It goes on to state that, when used in pregnancy, the patient should be apprised of the potential hazard to the fetus. While stating that no adequate and well-controlled studies have taken place in humans, it notes that, when given to animals in doses equivalent to human dosages, teratogenesis was observed. Transplant patients already on this drug should not discontinue on becoming pregnant. This contrasts to the later-developed drugs tacrolimus and myophenolate which are contra-indicated by the manufacturers during pregnancy. As for all cytotoxic drugs, the manufacturer advises not to breastfeed whilst taking azathioprine. The Lactation Risk Category (LAC) reported by Thomas Hale in "Medications and Mothers' Milk" lists azathioprine as "L3", termed "moderately safe".

Under FDA rules, this drug, like many others, excludes eligibility for blood donation.

External links

• Imuran (GlaxoSmithKline Patient Information Leaflet)
• Azasan (manufacturer's website)
• Medline Plus advice on Imuran ( A service of the National Institutes of Health)
• GSK Product Monograph for Imuran (for Canadian patients only)
• U.S. National Library of Medicine: Drug Information Portal - Azathioprine

de:Azathioprin fi:Atsatiopriini