Consult the medical resource doctors trust

UpToDate is one of the most respected medical information resources in the world, used by over 360,000 doctors and thousands of patients to find answers to medical questions.

  • Content written by a faculty of over 4,000 physicians from leading medical institutions
  • Unbiased: free of advertising or pharmaceutical funding
  • Evidence-based treatment recommendations
  • Continuously updated to incorporate new medical findings

Azathioprine and 6-mercaptopurine in ulcerative colitis

INTRODUCTION

Immunomodulatory drugs, such as azathioprine (AZA) and 6-mercaptopurine (6-MP) exert a steroid-sparing effect in patients with steroid-dependent ulcerative colitis [1]. Such patients are commonly encountered. In one review, up to 16 percent of patients with ulcerative colitis failed to respond to corticosteroids while 22 percent developed corticosteroid dependence [2].

However, there is a general reluctance to use these agents in such patients because of concerns related to toxicity and since cure is possible with colectomy. Despite these concerns, both drugs have been used safely for many years in the treatment of inflammatory bowel disease and a variety of other immune-mediated disorders. Patients with ulcerative colitis who do not desire surgery or those with more limited disease but with persistent or debilitating symptoms are particularly good candidates for long-term therapy with these drugs [3]. Furthermore, the risk of chronic pouchitis and evidence of significantly reduced fertility rates in women post-proctocolectomy [4] represent additional considerations for using these drugs in young patients.

This topic review summarizes the evidence regarding use of AZA and 6-MP in the treatment of ulcerative colitis. A general approach to ulcerative colitis is presented separately. (See "Medical management of ulcerative colitis" and "Management of ulcerative proctitis, proctosigmoiditis, and left-sided colitis" and "Surgical management of inflammatory bowel disease".)

PHARMACODYNAMICS

Azathioprine is a prodrug that is quickly converted to 6-MP via a non-enzymatic nucleophilic attack by sulfhydryl-containing compounds such as glutathione present in red blood cells and other tissues. 6-MP is then metabolized in the liver and gut by one of three enzymes (algorithm 1) [1,5]:

  • Thiopurine-S-methyltransferase (TPMT), which catalyses the methylation of 6-MP to an inactive metabolite 6-methyl-mercaptopurine (6-MMP)
  • Xanthine oxidase, which catalyses 6-MP to inactive thiourate
  • Hypoxanthine-guanine-phosphoribosyltransferase, which converts 6-MP to active metabolite 6-thioguanine (6-TG) nucleotides
To continue reading this article you need to subscribe.

Read the rest of this article and others like it

The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use (click here) ©2010 UpToDate, Inc.
References Top
  1. Nielsen, OH, Vainer, B, Rask-Madsen, J. Review article: the treatment of inflammatory bowel disease with 6-mercaptopurine or azathioprine. Aliment Pharmacol Ther 2001; 15:1699.
  2. Faubion, WA Jr, Loftus, EV Jr, Harmsen, WS, Zinsmeister, AR. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology 2001; 121:255.
  3. Ardizzone, S, Molteni, P, Imbesi, V, Bollani, S. Azathioprine in steroid-resistant and steroid-dependent ulcerative colitis. J Clin Gastroenterol 1997; 25:330.
  4. Ording Olsen, K, Juul, S, Berndtsson, I, et al. Ulcerative colitis: female fecundity before diagnosis, during disease, and after surgery compared with a population sample. Gastroenterology 2002; 122:15.
  5. Tremaine, WJ. Refractory IBD: medical management. Neth J Med 1997; 50:S12.
  6. Yatscoff, RW, Aspeslet, LJ. The monitoring of immunosuppressive drugs: a pharmacodynamic approach. Ther Drug Monit 1998; 20:459.
  7. Lennard, L. Assay of 6-thioinosinic acid and 6-thioguanine nucleotides, active metabolites of 6-mercaptopurine, in human red blood cells. J Chromatogr 1987; 423:169.
  8. Sandborn, WJ. A review of immune modifier therapy for inflammatory bowel disease: Azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate. Am J Gastroenterol 1996; 91:423.
  9. Lennard, L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol 1992; 43:329.
  10. 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.
  11. Weinshilboum, RM, Otterness, DM, Szumlanski, CL. Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. Annu Rev Pharmacol Toxicol 1999; 39:19.
  12. Cuffari, C, Hunt, S, Bayless, TM. Enhanced bioavailability of azathioprine compared to 6-mercaptopurine therapy in inflammatory bowel disease: correlation with treatment efficacy. Aliment Pharmacol Ther 2000; 14:1009.
  13. Pearson, DC, May, GR, Fick, GH, Sutherland, LR. Azathioprine and 6-mercaptopurine in Crohn's disease: a meta-analysis. Ann Intern Med 1995; 123:132.
  14. Cuffari, C, Hunt, S, Bayless, T. Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease. Gut 2001; 48:642.
  15. Keuzenkamp-Jansen, CW, DeAbreu, RA, Bokkerink, JP, Lambooy, MA. Metabolism of intravenously administered high-dose 6-mercaptopurine with and without allopurinol treatment in patients with non-Hodgkin lymphoma. J Pediatr Hematol Oncol 1996; 18:145.
  16. Rosenberg, JL, Wall, AJ, Levin, B, et al. A controlled trial of azathioprine in the management of chronic ulcerative colitis. Gastroenterology 1975; 69:96.
  17. Hawthorne, AB, Logan, RF, Hawkey, CJ, Foster, PN. Randomised controlled trial of azathioprine withdrawal in ulcerative colitis. BMJ 1992; 305:20.
  18. Sood, A, Midha, V, Sood, N, Kaushal, V. Role of azathioprine in severe ulcerative colitis: one-year, placebo-controlled, randomized trial. Indian J Gastroenterol 2000; 19:14.
  19. Sood, A, Kaushal, V, Midha, V, et al. The beneficial effect of azathioprine on maintenance of remission in severe ulcerative colitis. J Gastroenterol 2002; 37:270.
  20. Kirk, AP, Lennard-Jones, JE. Controlled trial of azathioprine in chronic ulcerative colitis. Br Med J (Clin Res Ed) 1982; 284:1291.
  21. Ardizzone, S, Maconi, G, Russo, A, et al. Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis. Gut 2006; 55:47.
  22. Jewell, DP, Truelove, SC. Azathioprine in ulcerative colitis: final report on controlled therapeutic trial. Br Med J 1974; 4:627.
  23. Timmer, A, McDonald, J, Macdonald, J. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2007; :CD000478.
  24. Andrews, JM, Travis, SP, Gibson, PR, Gasche, C. Systematic review: does concurrent therapy with 5-ASA and immunomodulators in inflammatory bowel disease improve outcomes?. Aliment Pharmacol Ther 2009; 29:459.
  25. Gisbert, JP, Linares, PM, McNicholl, AG, et al. Meta-analysis: the efficacy of azathioprine and mercaptopurine in ulcerative colitis. Aliment Pharmacol Ther 2009; 30:126.
  26. Campbell, S, Ghosh, S. Effective maintenance of inflammatory bowel disease remission by azathioprine does not require concurrent 5-aminosalicylate therapy. Eur J Gastroenterol Hepatol 2001; 13:1297.
  27. Mantzaris, GJ, Sfakianakis, M, Archavlis, E, et al. A Prospective Randomized Observer-Blind 2-Year Trial of Azathioprine Monotherapy versus Azathioprine and Olsalazine for the Maintenance of Remission of Steroid-Dependent Ulcerative Colitis. Am J Gastroenterol 2004; 99:1122.
  28. Sandborn, WJ, Tremaine, WJ, Wolf, DC, Targan, SR. Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease. North American Azathioprine Study Group. Gastroenterology 1999; 117:527.
  29. Mahadevan, U, Tremaine, WJ, Johnson, T, Pike, MG. Intravenous azathioprine in severe ulcerative colitis: a pilot study. Am J Gastroenterol 2000; 95:3463.
  30. Bowen, DG, Selby, WS. Use of 6-mercaptopurine in patients with inflammatory bowel disease previously intolerant of azathioprine. Dig Dis Sci 2000; 45:1810.
  31. Boulton-Jones, JR, Pritchard, K, Mahmoud, AA. The use of 6-mercaptopurine in patients with inflammatory bowel disease after failure of azathioprine therapy. Aliment Pharmacol Ther 2000; 14:1561.
  32. Korelitz, BI, Zlatanic, J, Goel, F, Fuller, S. Allergic reactions to 6-mercaptopurine during treatment of inflammatory bowel disease. J Clin Gastroenterol 1999; 28:341.
  33. George, J, Present, DH, Pou, R, et al. The longterm outcome of ulcerative colitis treated with 6-mercaptopurine. Am J Gastroenterol 1996; 91:1711.
  34. Fraser, AG, Orchard, TR, Jewell, DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut 2002; 50:485.
  35. Tanis, AA. Azathioprine in inflammatory bowel disease, a safe alternative?. Mediators Inflamm 1998; 7:141.
  36. Cuffari, C, Theoret, Y, Latour, S, Seidman, G. 6-Mercaptopurine metabolism in Crohn's disease: correlation with efficacy and toxicity. Gut 1996; 39:401.
  37. Dubinsky, MC, Lamothe, S, Yang, HY, et al. Pharmacogenetics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 2000; 118:705.
  38. Connell, WR, Kamm, MA, Dickson, M, et al. Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet 1994; 343:1249.
white circle LOG IN
white circle DEMO