| Systematic (IUPAC) name | |
|---|---|
| 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)sulfanyl]-7H-purine | |
| Clinical data | |
| Pregnancy cat. | D |
| Legal status | ℞ Prescription only |
| Routes | oral |
| Pharmacokinetic data | |
| Bioavailability | Well absorbed |
| Metabolism | By xanthine oxidase |
| Half-life | 3 hours |
| Excretion | Renal, minimally |
| Identifiers | |
| CAS number | 446-86-6 |
| ATC code | L04AX01 |
| PubChem | CID 2265 |
| DrugBank | APRD00811 |
| ChemSpider | 2178 |
| UNII | MRK240IY2L |
| KEGG | D00238 |
| ChEBI | CHEBI:2948 |
| ChEMBL | CHEMBL1542 |
| Chemical data | |
| Formula | C9H7N7O2S |
| Mol. mass | 277.263 g/mol |
| SMILES | eMolecules & PubChem |
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Azathioprine (/ˌæzəˈθaɪɵpriːn/) is a purine analogue immunosuppressive drug. It is used to prevent organ rejection following organ transplantation and to treat a vast array of autoimmune diseases, including rheumatoid arthritis, pemphigus, inflammatory bowel disease (such as Crohn's disease and ulcerative Colitis), multiple sclerosis, autoimmune hepatitis, atopic dermatitis, Myasthenia Gravis, Neuromyelitis optica / NMO / Devic, restrictive lung disease, and others.
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,the U.S., Australia, Ireland and Great Britain, Azamun in Finland and Imurel in Scandinavia and France).
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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 and 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.
Azathioprine is a pro-drug. Following oral ingestion, it is metabolized into the active 6-mercaptopurine, itself a purine synthesis inhibitor. 6-Mercaptopurine impedes DNA synthesis and thus inhibits the proliferation of cells, especially the fast-growing lymphocytes. T-cells and B-cells are particularly affected by the inhibition of purine synthesis. Azathioprine is an effective drug used alone in certain autoimmune diseases, or in combination with other immunosuppressants in organ transplantation. Azathioprine blocks the downstream affects of CD28 costimulation. 6-MP (the active metabolite) interacts directly with GTP-binding protein Rac1, thus blocking upregulation of BCL-xl mRNA and protein. In vivo data indicates that inflammatory bowel disease patients treated with azathioprine have more apoptotic mononuclear cells than untreated controls, indicating that this mechanism may be responsible for the in vivo response to the drug in this disease.[1]
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. Acute pancreatitis can also occur, especially in patients with Crohn's disease.[2] 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 avoid this complication.[3]
Ciclosporin has nowadays replaced some of the azathioprine use due to less side effects, especially in heart-related transplatations.[4][5][6] Moreover, despite being 15 times more expensive,[7] Mycophenolate mofetil is also 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.[8] However, azathioprine certainly still has a major role.
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.[9] In the 12th and current report, it is asserted that azathioprine is "known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans."[10] Furthermore,as is detailed below, additional post-marketing experience has meant that the U.S. Food and Drug Administration (FDA) has required warnings to be placed on packaging with respect to increased risks of certain cancers.
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,[11] although the methodology of past studies and the possible underlying mechanisms are questioned.[12] 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.[13]
Cases of hepatosplenic T-cell lymphoma (HSTCL) - a rare type of T-cell 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 major cohort of cases. 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.[14]
While Azathioprine had not been thought to cause fetal malformation (teratogenesis) and that any risk to the offspring of treated women is small, [15] 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 mycophenolate which are contra-indicated by the manufacturers during pregnancy.[15] 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.[16]
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