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Pharmacology and side effects of azathioprine when used in rheumatic diseases

Author
H Michael Belmont, MD
Section Editor
Daniel E Furst, MD
Deputy Editor
Paul L Romain, MD

INTRODUCTION

Azathioprine (AZA) is an immunosuppressive agent that acts through its effects as an antagonist of purine metabolism, resulting in the inhibition of DNA, RNA, and protein synthesis. It has been used as an immunosuppressive agent for the treatment of a variety of disorders, including a number of rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), dermatomyositis and polymyositis, systemic sclerosis, and systemic vasculitis; for the treatment of inflammatory bowel disease and other conditions; and for the prevention of organ transplant rejection.

The pharmacology and adverse effects of AZA, particularly when used in the context of the rheumatic diseases, will be reviewed here. The role of AZA in the management of the different rheumatic diseases and other autoimmune and immune-mediated disorders, and for the prevention and management of transplant rejection, is presented in detail separately in the appropriate topic reviews covering the treatment of these individual conditions.

PHARMACOLOGY

Azathioprine (AZA) is the 1-methyl-4-nitro-5-imidazolyl derivative of thioguanine, a purine-mimic antimetabolite [1]. It is well-absorbed from the gastrointestinal tract and has a serum half-life of 0.2 to 0.5 hours, resulting in a biologic half-life of approximately 24 hours [2]. AZA is a prodrug; the action of glutathione in red blood cells causes the formation of the principal metabolite 6-mercaptopurine (6-MP) [1].

Metabolism — The prodrug AZA is approximately 30 percent protein-bound. Forty-five percent of the drug is excreted in the urine; the remainder is metabolized to 6-MP, which is then further metabolized along competing routes:

It undergoes catabolic oxidation to 6-thiouric acid, which is an inactive metabolite. This reaction is catalyzed by xanthine oxidase, which is concentrated in the intestine and liver.

                

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Literature review current through: Aug 2017. | This topic last updated: Sep 08, 2017.
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References
Top
  1. Elion GB. The purine path to chemotherapy. Science 1989; 244:41.
  2. Huskisson EC. Azathioprine. Clin Rheum Dis 1984; 10:325.
  3. Lennard L, Van Loon JA, Weinshilboum RM. Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther 1989; 46:149.
  4. Black AJ, McLeod HL, Capell HA, et al. Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann Intern Med 1998; 129:716.
  5. Jun JB, Cho DY, Kang C, Bae SC. Thiopurine S-methyltransferase polymorphisms and the relationship between the mutant alleles and the adverse effects in systemic lupus erythematosus patients taking azathioprine. Clin Exp Rheumatol 2005; 23:873.
  6. Relling MV, Hancock ML, Rivera GK, et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 1999; 91:2001.
  7. Askanase AD, Wallace DJ, Weisman MH, et al. Use of pharmacogenetics, enzymatic phenotyping, and metabolite monitoring to guide treatment with azathioprine in patients with systemic lupus erythematosus. J Rheumatol 2009; 36:89.
  8. Stocco G, Martelossi S, Barabino A, et al. Glutathione-S-transferase genotypes and the adverse effects of azathioprine in young patients with inflammatory bowel disease. Inflamm Bowel Dis 2007; 13:57.
  9. Kaczmorski S, Doares W, Winfrey S, et al. Gout and transplantation: new treatment option-same old drug interaction. Transplantation 2011; 92:e13.
  10. US Food and Drug Administration. Uloric (febuxostat tablets). Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm243770.htm (Accessed on May 06, 2014).
  11. Elion GB, Hitchings GH. Azathioprine. Handbook Exp Pharmacol 1975; 38:404.
  12. McKendry RJR. Pruine analogues. In: Second Line Agents in the Treatment of Rheumatic Diseases, Dixon J, Furst BE (Eds), Marcel Decker, New York 1991.
  13. Trotter JL, Rodey GE, Gebel HM. Azathioprine decreases suppressor T cells in patients with multiple sclerosis. N Engl J Med 1982; 306:365.
  14. Bacon PA, Salmon M. Modes of action of second-line agents. Scand J Rheumatol Suppl 1987; 64:17.
  15. Crilly A, McInnes IB, Capell HA, Madhok R. The effect of azathioprine on serum levels of interleukin 6 and soluble interleukin 2 receptor. Scand J Rheumatol 1994; 23:87.
  16. Tiede I, Fritz G, Strand S, et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest 2003; 111:1133.
  17. Poppe D, Tiede I, Fritz G, et al. Azathioprine suppresses ezrin-radixin-moesin-dependent T cell-APC conjugation through inhibition of Vav guanosine exchange activity on Rac proteins. J Immunol 2006; 176:640.
  18. Nyhan WL, Sweetman L, Carpenter DG, et al. Effects of azathiprine in a disorder of uric acid metabolism and cerebral function. J Pediatr 1968; 72:111.
  19. Currey HL, Harris J, Mason RM, et al. Comparison of azathioprine, cyclophosphamide, and gold in treatment of rheumatoid arthritis. Br Med J 1974; 3:763.
  20. Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 1980; 32:651.
  21. Van Loon JA, Weinshilboum RM. Thiopurine methyltransferase biochemical genetics: human lymphocyte activity. Biochem Genet 1982; 20:637.
  22. Woodson LC, Dunnette JH, Weinshilboum RM. Pharmacogenetics of human thiopurine methyltransferase: kidney-erythrocyte correlation and immunotitration studies. J Pharmacol Exp Ther 1982; 222:174.
  23. Ragab AH, Gilkerson E, Myers M. The effect of 6-mercaptopurine and allopurinol on granulopoiesis. Cancer Res 1974; 34:2246.
  24. Pinals RS. Azathioprine in the treatment of chronic polyarthritis: longterm results and adverse effects in 25 patients. J Rheumatol 1976; 3:140.
  25. Singh G, Fries JF, Spitz P, Williams CA. Toxic effects of azathioprine in rheumatoid arthritis. A national post-marketing perspective. Arthritis Rheum 1989; 32:837.
  26. Mok MY, Ng WL, Yuen MF, et al. Safety of disease modifying anti-rheumatic agents in rheumatoid arthritis patients with chronic viral hepatitis. Clin Exp Rheumatol 2000; 18:363.
  27. Bernatsky S, Clarke AE, Suissa S. Hematologic malignant neoplasms after drug exposure in rheumatoid arthritis. Arch Intern Med 2008; 168:378.
  28. Silman AJ, Petrie J, Hazleman B, Evans SJ. Lymphoproliferative cancer and other malignancy in patients with rheumatoid arthritis treated with azathioprine: a 20 year follow up study. Ann Rheum Dis 1988; 47:988.
  29. Asten P, Barrett J, Symmons D. Risk of developing certain malignancies is related to duration of immunosuppressive drug exposure in patients with rheumatic diseases. J Rheumatol 1999; 26:1705.
  30. Kaiser R. Incidence of lymphoma in patients with rheumatoid arthritis: a systematic review of the literature. Clin Lymphoma Myeloma 2008; 8:87.
  31. Penn I. Cancers complicating organ transplantation. N Engl J Med 1990; 323:1767.