Azathioprine

Source: Wikipedia, the free encyclopedia.
Azathioprine
Clinical data
Pronunciation/ˌæzəˈθəˌprn/[1]
Trade namesAzasan, Imuran, Jayempi, others
Other namesAZA
AHFS/Drugs.comMonograph
MedlinePlusa682167
License data
Pregnancy
category
  • AU: D
By mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability60±31%
Protein binding20–30%
MetabolismActivated non-enzymatically, deactivated mainly by xanthine oxidase
Elimination half-life26–80 minutes (azathioprine)
3–5 hours (drug plus metabolites)
ExcretionKidney, 98% as metabolites
Identifiers
  • 6-[(1-Methyl-4-nitro-1H-imidazol-5-yl)sulfanyl]-7H-purine
JSmol)
Melting point238 to 245 °C (460 to 473 °F)
  • Cn1cnc(N(=O)=O)c1Sc2ncnc3nc[nH]c23
  • InChI=1S/C9H7N7O2S/c1-15-4-14-7(16(17)18)9(15)19-8-5-6(11-2-10-5)12-3-13-8/h2-4H,1H3,(H,10,11,12,13) checkY
  • Key:LMEKQMALGUDUQG-UHFFFAOYSA-N checkY
  (verify)

Azathioprine, sold under the brand name Imuran, among others, is an

injected into a vein.[5]

Common side effects include

6-thioguanine to disrupt the making of RNA and DNA by cells.[5][9]

Azathioprine was first made in 1957.[9] It is on the World Health Organization's List of Essential Medicines.[10] In 2018, it was the 358th most commonly prescribed medication in the United States, with more than 800,000 prescriptions.[11]

Medical uses

Azathioprine is used alone or in combination with other immunosuppressive therapy to prevent rejection following organ transplantation, and to treat an array of

neuromyelitis optica (Devic's disease), restrictive lung disease, and others.[12] It is also an important therapy and steroid-sparing agent for inflammatory bowel disease (such as Crohn's disease and ulcerative colitis) and for multiple sclerosis.[13]

In the United States, it is approved by the Food and Drug Administration for use in kidney transplantation from human donors, and for rheumatoid arthritis.[14]

Transplantation

Azathioprine is used to prevent rejections of kidney or liver

corticosteroids, other immunosuppressants, and local radiation therapy.[15][16] The administration protocol starts either at the time of transplantation or within the following two days.[14]

Rheumatoid arthritis

Being a

Nonsteroidal anti-inflammatory drugs and corticosteroids may be combined or continued (if they were already in use) with azathioprine, but the combination with other DMARDs is not recommended.[14]

Inflammatory bowel disease

Azathioprine has been used in the management of moderate to severe chronically active Crohn's disease,

clinical remission (absence of disease activity) in corticosteroid-dependent patients,[19] and to provide benefit in people with fistulizing Crohn's disease.[20] The onset of action is slow, and it may require several months to achieve clinical response.[18]

Azathioprine treatment is associated with an increased risk of lymphoma, but if this is due to the drug or a predisposition related to Crohn's disease is unclear.[21] Lower doses of azathioprine are used as a therapy in children with refractory or corticosteroid-dependent Crohn's disease, without causing many side effects.[22] It may also be used to prevent flares in those with ulcerative colitis.[23]

Others

Azathioprine is sometimes used in systemic lupus erythematosus, requiring a maintenance dose of 15 mg or higher of prednisone in those who experience recurrent flares.[24]

It is used as an add-on therapy when steroid therapy is given by mouth for pemphigus and myasthenia gravis, as a "steroid-sparing" agent.[12][25][26] Azathioprine is also used to maintain remission in people who have granulomatosis with polyangiitis.[7]

It can be very effective in eczema and atopic dermatitis, though it is not commonly used.[12] The British National Eczema Society lists it as a third-line treatment for severe to moderate cases of these skin diseases.[27]

It was widely used for the treatment of multiple sclerosis until the first half of the 1990s. Concerns about increased risk of

interferon beta, conflicting conclusions regarding cancer, and the potential for long-term risks.[29]

A widely used therapy for idiopathic pulmonary fibrosis was azathioprine in combination with prednisone and N-acetylcysteine. A 2012 study showed that outcomes were worse with this combination than with placebo.[30]

Adverse effects

Two generic azathioprine oral tablets, 50 mg each

Nausea and vomiting are common adverse effects, especially at the beginning of a treatment. Such cases are met with taking azathioprine after meals or transient

blood count is recommended during treatment.[14][31] Acute pancreatitis can also occur, especially in patients with Crohn's disease.[32] Treatment is discontinued in up to 30% of patients due these effects but therapeutic drug monitoring of the biologically active metabolites, i.e. thiopurine nucleotides can help to optimize the efficacy and safety. Clinically, most hospitals resort to on-exchange LC-MS (liquid chromotography – mass spectrometry) but the newly developed approach of porous graphitic carbon based chromatography hyphenated with mass spectrometry appears superior with respect to patient care in this respect.[33]

It is listed by the

group 1 carcinogen (carcinogenic to humans).[34]

Pharmacogenetics

The enzyme

pharmacogenetics being translated into routine clinical care.[43] Missense SNP in NUDT15 (e.g., rs116855232, inducing R139C)) has been identified to be a causal factor for AZA-induced leukopenia through a genome wide association study (GWAS) in East Asians.[44]

Cancers

Azathioprine is listed as a human carcinogen in the 12th Report on Carcinogens by the National Toxicology Program of U.S. Department of Health and Human Services, asserting that it is "known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans."[45] Since August 2009, the U.S. FDA has required warnings to be placed on packaging with respect to increased risks of certain cancers.[46]

The risks involved seem to be related both to the duration and the dosage used. People who have previously been treated with an

group 1),[47] although the methodology of past studies and the possible underlying mechanisms are questioned.[48]

The various diseases requiring transplantation may in themselves increase the risks of

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 lower risk than those undergoing transplantation.[34]

Cases of hepatosplenic T-cell lymphoma – a rare type of 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 majority of cases.[49] 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.[50]

Skin cancers

In transplant patients,

ultraviolet light. Patients taking azathioprine were found to be abnormally sensitive to UVA light.[52]

Overdose

Large single doses are generally well tolerated; a patient who took 7.5 g azathioprine (150 tablets) at once showed no relevant symptoms apart from vomiting, slightly decreased white blood cell count, and marginal changes in liver function parameters. Main symptoms of long-term overdosing are infections of unclear origin, mouth ulcers, and spontaneous bleeding, all of which are consequences of its bone-marrow suppression.[31]

Interactions

Other purine analogues, such as allopurinol, inhibit xanthine oxidase, the enzyme that breaks down azathioprine, thus increasing the toxicity of azathioprine.[53] Low doses of allopurinol, though, have been shown to safely enhance the efficacy of azathioprine, especially in inflammatory bowel disease nonresponders.[54][55][56] This may still lead to lower lymphocyte counts and higher rates of infection, therefore the combination requires careful monitoring.[57][58]

Azathioprine decreases the effects of the

niacin (vitamin B3), resulting in at least one case to pellagra and fatal medullary aplasia.[59]

Pregnancy and breastfeeding

Azathioprine can cause birth defects.

well-controlled studies have taken place in humans, when given to animals in doses equivalent to human dosages, teratogenesis was observed.[65] Transplant patients already on this drug should not discontinue on becoming pregnant. This contrasts with the later-developed drugs tacrolimus and mycophenolate, which are contraindicated during pregnancy.[60]

Traditionally, as for all

cytotoxic drugs, the manufacturer advises not to breastfeed whilst taking azathioprine, but the "lactation risk category" reported by Thomas Hale in his book Medications and Mothers' Milk lists azathioprine as "L3", termed "moderately safe".[66]

Pharmacology

Pharmacokinetics

thioinosine monophosphate, thioinosinic acid
  • MeTIMP: methyl-thioinosine monophosphate
  • TGTP: thioguanosine triphosphate
  • TdGTP: thio-deoxyguanosine triphosphate
  • Azathioprine is absorbed from the gut to about 88%.

    plasma proteins while circulating in the bloodstream.[12][31][69][70]

    Azathioprine is a

    hydroxylated purines, which are excreted via the urine.[40][69][70]

    Mechanism of action

    Azathioprine inhibits purine synthesis. Purines are needed to produce DNA and RNA. By inhibiting purine synthesis, less DNA and RNA are produced for the synthesis of white blood cells, thus causing immunosuppression.

    Azathioprine is converted within tissues to 6-MP, some of which is converted, in turn, to

    guanylic acid
    ; the former is the starting point for purine nucleotide biosynthesis, while the latter is one of the building blocks of DNA and RNA.

    Chemistry

    Azathioprine is a

    hydrolyzes to 6-mercaptopurine.[69]

    Azathioprine is synthesized from 5-chloro-1-methyl-4-nitro-1H-imidazole and 6-mercaptopurine in

    nitro group is introduced with nitric and sulfuric acid
    .

    The whole process of azathioprine synthesis

    History

    Azathioprine was synthesized by

    Gertrude Elion in 1957 (named BW 57-322) to produce 6-MP in a metabolically active, but masked form, and at first used as a chemotherapy drug.[75][76][77]

    Robert Schwartz investigated the effect of 6-MP on the immune response in 1958 and discovered that it profoundly suppresses the formation of

    heart transplants.[79] When Calne asked Elion for related compounds to investigate, she suggested azathioprine, which was subsequently found out to be superior (as effective and less toxic to the bone marrow) by Calne.[75][12]

    In April 1962, with regimens consisting of azathioprine and prednisone, the transplantation of kidneys to unrelated recipients (allotransplantation) was successful for the first time.[12][80] For many years, this kind of dual therapy with azathioprine and glucocorticoids was the standard antirejection regimen, until ciclosporin was introduced into clinical practice (by Calne as well) in 1978.

    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.[16][84]

    References

    1. ^ "Azathioprine". Merriam-Webster.com Dictionary.
    2. FDA
      . Retrieved 22 Oct 2023.
    3. ^ "Jayempi EPAR". European Medicines Agency. 20 April 2021. Retrieved 4 March 2023.
    4. ^ "Jayempi Product information". Union Register of medicinal products. Retrieved 3 March 2023.
    5. ^ a b c d e f g h i "Azathioprine". The American Society of Health-System Pharmacists. Archived from the original on 20 August 2016. Retrieved 8 December 2016.
    6. PMID 27239106
      .
    7. ^ .
    8. .
    9. ^ from the original on 2016-12-21.
    10. . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
    11. ^ "Azathioprine - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
    12. ^
      PMID 16908341
      .
    13. ^ .
    14. ^ .
    15. .
    16. ^ .
    17. .
    18. ^ .
    19. .
    20. .
    21. .
    22. .
    23. .
    24. .
    25. .
    26. .
    27. .
    28. .
    29. .
    30. .
    31. ^ .
    32. .
    33. .
    34. ^ a b International Agency for Research on Cancer (IARC) (1987). "Azathioprine". Summaries & Evaluations (suppl. 7): 119. Archived from the original on 2006-06-04.
    35. PMID 28520349
      . Bookshelf ID: NBK100661.
    36. ^ .
    37. .
    38. PMID 17691917. Archived from the original
      on 2013-01-12.
    39. ^ .
    40. ^ .
    41. .
    42. ^ "Label: Imuran - azathioprine tablet". Archived from the original on 20 October 2014. Retrieved 19 October 2014.
    43. PMID 20154640
      .
    44. .
    45. ^ National Toxicology Program (10 June 2011). "Report On Carcinogens – Twelfth Edition – 2011". National Toxicology Program. Archived (PDF) from the original on 16 July 2012. Retrieved June 20, 2012.
    46. ^ "FDA: Cancer Warnings Required for TNF Blockers". FDA. August 4, 2009. Archived from the original on July 3, 2012. Retrieved June 20, 2012.
    47. ^ International Agency for Research on Cancer (IARC) (1981). "Azathioprine – 5. Summary of Data Reported and Evaluation". Summaries & Evaluations. 26: 47. Archived from the original on 2006-09-06.
    48. PMID 7683109
      .
    49. .
    50. ^ "Imuran (azathioprine) Tablets and Injection". FDA. May 2011. Archived from the original on March 2, 2012. Retrieved June 20, 2012.
    51. ^ "Skin cancer alert for organ drug". BBC Online. BBC News. September 15, 2005. Archived from the original on October 14, 2012. Retrieved June 10, 2012.
    52. PMID 16166520
      .
    53. .
    54. .
    55. .
    56. .
    57. .
    58. .
    59. .
    60. ^ .
    61. .
    62. .
    63. .
    64. .
    65. .
    66. .
    67. .
    68. .
    69. ^ .
    70. ^ .
    71. ^ "Azathioprine Pathway". Small Molecule Pathway Database. Archived from the original on 2 July 2012. Retrieved 31 August 2012.
    72. ^
      PMID 12697731
      .
    73. ^ US Patent 3056785, G. H. Hitchings; Yonkers & G. B. Elion, "Purine Derivatives", issued 1962-10-06 .
    74. .
    75. ^ .
    76. .
    77. .
    78. .
    79. .
    80. .
    81. .
    82. .
    83. .
    84. .

    Further reading