Azathioprine

Encyclopedia : A : AZ : AZA : Azathioprine

Azathioprine is a chemotherapy drug, now rarely used for chemotherapy but more for immunosuppression in organ transplantation, autoimmune disease such as rheumatoid arthritis or inflammatory bowel disease such as Crohn's disease. It is a pro-drug, converted in the body to the active metabolites 6-mercaptopurine and 6-thioinosinic acid.

Azathioprine is produced by a number of generic manufacturers and as branded names (Azasan® by Salix in US and Imuran® by GlaxoSmithKline in UK).

Contents

1 History
2 Mechanism of action
3 Long term side effects
4 References
5 External links

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. 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 acts to inhibit purine synthesis necessary for the proliferation of cells, especially leukocytes and lymphocytes. It is an effective drug used alone in certain autoimmune diseases, or in combination with other immunosuppressants in organ transplantation. Its most severe side effect is bone marrow suppression, and it should not be given 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. 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

It is listed as a human carcinogen in the 11th Report on Carcinogens of the US Department of Health and Human Sciences, 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 dosage used. People who 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 dieases 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. Interestingly 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 men is small.British National Formulary 45 March 2003 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, it is advised not to breastfeed whilst taking azathioprine.

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

References

External links

[Imuran®] (Glaxo Leafet)
[Azasan®] (manufacturer's website)

For a full list of external links to MSDSs, spectroscopic data, commercial chemicals suppliers etc. for this compound, see [Chemical sources].

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