Azathioprine
From Wikipedia, the free encyclopedia
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| Azathioprine
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| Systematic (IUPAC) name | |
| 6-(3-methyl-5-nitro-imidazol-4-yl)sulfanyl-7H-purine | |
| Identifiers | |
| CAS number | 446-86-6 |
| ATC code | L04AX01 |
| PubChem | 2265 |
| DrugBank | APRD00811 |
| Chemical data | |
| Formula | C9H7N7O2S |
| Mol. weight | 277.264 |
| Pharmacokinetic data | |
| Bioavailability | Well absorbed |
| Metabolism | ? |
| Half life | Approximately 5 hours for the unchanged drug and its metabolites. |
| Excretion | ? |
| Therapeutic considerations | |
| Pregnancy cat. |
D |
| Legal status |
Approved Drug |
| Routes | oral |
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 Canada and UK).
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[edit] 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.
[edit] 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 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.<ref name="BMJ2005-Konstantopoulou">Konstantopoulou M, Belgi A, Griffiths K, Seale J, Macfarlane A (2005). "Azathioprine-induced pancytopenia in a patient with pompholyx and deficiency of erythrocyte thiopurine methyltransferase.". BMJ 330 (7487): 350-1. PMID 15705694.</ref>
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.<ref name="HealthTechnolAssess2005-Woodroffe">Woodroffe R, Yao G, Meads C, Bayliss S, Ready A, Raftery J, Taylor R (2005). "Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study.". Health Technol Assess 9 (21): 1-194. PMID 15899149.</ref> However azathioprine certainly still has a major role.
[edit] 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.<ref name="NTP">National Toxicology Program. “Azathioprine”, Substance Profiles, Report on Ccarcinogens, Eleventh Edition, U.S. Department of Health and Human Services.</ref> 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,<ref name="IARC-1981">International Agency for Research on Cancer (IARC) (1987). Azathioprine - 5. Summary of Data Reported and Evaluation. Summaries & Evaluations pp. VOL.: 26 (1981) (p. 47). World Health Organization.</ref> although the methodology of past studies and the possible underlying mechanisms are questioned.<ref name="MutatRes1993-Gombar">Gombar V, Enslein K, Blake B, Einstein K (1993). "Carcinogenicity of azathioprine: an S-AR investigation.". Mutat Res 302 (1): 7-12. PMID 7683109.</ref> 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.<ref name="IARC-1987">International Agency for Research on Cancer (IARC) (1987). Azathioprine - Evidence for carcinogenicity to humans (sufficient). Summaries & Evaluations pp. Supplement 7: (1987) (p. 119). World Health Organization.</ref>
Azathioprine is not thought to cause fetal malformation (teratogenesis) and any risk to the offspring of treated men is small.<ref name="BNF">British National Formulary 45 March 2003</ref> 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 say 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 teratogenic 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.<ref name="BNF"/> 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.
[edit] References
<references/>
[edit] External links
- Imuran® (Glaxo Leafet)
- Azasan® (manufacturer's website)
- Medline Plus advice on Imuran ( A service of the National Institutes of Health)
- GKS Product Monograph for Imuran
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