Azathioprine

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Azathioprine structure.svg
Azathioprine
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. mass 277.264 g/mol
Pharmacokinetic data
Bioavailability Well absorbed
Metabolism  ?
Half life 3hr
Excretion renal, minimally
Therapeutic considerations
Pregnancy cat.

D

Legal status

Approved Drug

Routes oral

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]


Overview

Azathioprine is an immunosupressant used in organ transplantation, autoimmune disease such as rheumatoid arthritis or inflammatory bowel disease such as Crohn's disease and ulcerative colitis. 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 the U.S., Imuran by GlaxoSmithKline in Canada and the U.S., Australia and UK and Azamun in Finland).

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. Side effects are uncommon, but include nausea, HA and rash. Because azathioprine suppresses the bone marrow, patients will be more susceptable 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.[1]

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.[2] However azathioprine certainly still has a major role.

Long term side effects

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.[3] 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,[4] although the methodology of past studies and the possible underlying mechanisms are questioned.[5] 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.[6]

Azathioprine is not thought to cause fetal malformation (teratogenesis) and any risk to the offspring of treated men is small.[7] 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 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.[7] As for all cytotoxic drugs, it is advised not to breastfeed whilst taking azathioprine.

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

Pill Images

Drug Name: Azathioprine
Ingredient(s): AZATHIOPRINE[AZATHIOPRINE]
Imprint: 54;043
Dosage: 50 mg
Color(s): Yellow
Shape: Round
Size (mm): 1
Score: 2
NDC:00544084

Drug Label Author: Roxane Laboratories, Inc

This pill image is provided by the National Library of Medicine's PillBox.

Drug Name: Azathioprine
Ingredient(s): AZATHIOPRINE[AZATHIOPRINE]
Imprint: 54;043
Dosage: 50 mg
Color(s): Yellow
Shape: Round
Size (mm): 1
Score: 2
NDC:00548084

Drug Label Author: Roxane Laboratories, Inc

This pill image is provided by the National Library of Medicine's PillBox.

Drug Name: Azathioprine
Ingredient(s): AZATHIOPRINE[AZATHIOPRINE]
Imprint: A;Z
Dosage: 50 mg
Color(s): Yellow
Shape: Round
Size (mm): 8
Score: 2
NDC:03781005

Drug Label Author: Mylan Pharmaceuticals Inc.

This pill image is provided by the National Library of Medicine's PillBox.

Drug Name: Azathioprine
Ingredient(s): AZATHIOPRINE[AZATHIOPRINE]
Imprint: 54;043
Dosage: 50 mg
Color(s): Yellow
Shape: Round
Size (mm): 1
Score: 2
NDC:433530686

Drug Label Author: Aphena Pharma Solutions - Tennessee, Inc.

This pill image is provided by the National Library of Medicine's PillBox.

Drug Name: Azathioprine
Ingredient(s): AZATHIOPRINE[AZATHIOPRINE]
Imprint: ZC;59
Dosage: 50 mg
Color(s): Yellow
Shape: Round
Size (mm): 8
Score: 2
NDC:683820003

Drug Label Author: Zydus Pharmaceuticals (USA) Inc.

This pill image is provided by the National Library of Medicine's PillBox.
IMURAN NDC 654830590.jpg

Drug Name: IMURAN
Ingredient(s): azathioprine[azathioprine]
Imprint: IMURAN;50
Dosage: 50 mg
Color(s): Yellow
Shape: DoubleCircle
Size (mm): 11
Score: 2
NDC:654830590

Drug Label Author: Prometheus Laboratories Inc.

This pill image is provided by the National Library of Medicine's PillBox.







References

  1. 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.
  2. 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.
  3. National Toxicology Program. "Azathioprine", Substance Profiles, Report on Ccarcinogens, Eleventh Edition, U.S. Department of Health and Human Services. 
  4. International Agency for Research on Cancer (IARC) (1987). Azathioprine - 5. Summary of Data Reported and Evaluation. Summaries & Evaluations VOL.: 26 (1981) (p. 47). World Health Organization.
  5. Gombar V, Enslein K, Blake B, Einstein K (1993). "Carcinogenicity of azathioprine: an S-AR investigation.". Mutat Res 302 (1): 7-12. PMID 7683109.
  6. International Agency for Research on Cancer (IARC) (1987). Azathioprine - Evidence for carcinogenicity to humans (sufficient). Summaries & Evaluations Supplement 7: (1987) (p. 119). World Health Organization.
  7. 7.0 7.1 British National Formulary 45 March 2003

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de:Azathioprinnl:Azathioprinefi:Atsatiopriini



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