Azathioprine and 6-mercaptopurine in inflammatory bowel disease
- Yousif I A-Rahim, MD, PhD
Yousif I A-Rahim, MD, PhD
- Instructor of Medicine
- Harvard Medical School
- Richard J Farrell, MD
Richard J Farrell, MD
- Gastroenterology Consultant, Connolly Hospital
- Associate Clinical Professor, Royal College of Surgeons in Ireland
Immunomodulatory drugs, such as azathioprine (AZA) and 6-mercaptopurine (6-MP), exert a steroid-sparing effect in patients with steroid-dependent and steroid-refractory inflammatory bowel disease. While azathioprine (AZA) and 6-mercaptopurine (6-MP) have been noted to induce and maintain remission in ulcerative colitis and Crohn disease, their use is limited by concerns of toxicity.
This topic review summarizes the pharmacology, dosing, monitoring, and adverse effects of AZA and 6-MP in inflammatory bowel disease. 6-MP metabolite monitoring and thiopurine-S-methyltransferase (TPMT) testing in the treatment of inflammatory bowel disease, indications and efficacy of AZA and 6-MP in ulcerative colitis and Crohn disease are presented separately. (See "6-mercaptopurine (6-MP) metabolite monitoring and TPMT testing in the treatment of inflammatory bowel disease with 6-MP or azathioprine" and "Approach to adults with steroid-refractory and steroid-dependent ulcerative colitis" and "Immunomodulator therapy in Crohn disease" and "Overview of the medical management of severe or refractory Crohn disease in adults".)
Azathioprine (AZA) is a prodrug that is quickly converted to 6-mercaptopurine (6-MP) via a nonenzymatic 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 (figure 1) [1,2]:
●Thiopurine-S-methyltransferase (TPMT), which catalyzes the methylation of 6-MP to an inactive metabolite 6-methyl-mercaptopurine (6-MMP)
●Xanthine oxidase, which catalyzes 6-MP to inactive thiourate
- 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.
- Tremaine WJ. Refractory IBD: medical management. Neth J Med 1997; 50:S12.
- Yatscoff RW, Aspeslet LJ. The monitoring of immunosuppressive drugs: a pharmacodynamic approach. Ther Drug Monit 1998; 20:459.
- 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.
- Sandborn WJ. A review of immune modifier therapy for inflammatory bowel disease: azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate. Am J Gastroenterol 1996; 91:423.
- Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol 1992; 43:329.
- 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.
- Weinshilboum RM, Otterness DM, Szumlanski CL. Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. Annu Rev Pharmacol Toxicol 1999; 39:19.
- 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.
- Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. Ann Intern Med 1995; 123:132.
- 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.
- Govani SM, Higgins PD. Combination of thiopurines and allopurinol: adverse events and clinical benefit in IBD. J Crohns Colitis 2010; 4:444.
- Keuzenkamp-Jansen CW, DeAbreu RA, Bökkerink JP, et al. 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.
- Szumlanski CL, Weinshilboum RM. Sulphasalazine inhibition of thiopurine methyltransferase: possible mechanism for interaction with 6-mercaptopurine and azathioprine. Br J Clin Pharmacol 1995; 39:456.
- Shih DQ, Nguyen M, Zheng L, et al. Split-dose administration of thiopurine drugs: a novel and effective strategy for managing preferential 6-MMP metabolism. Aliment Pharmacol Ther 2012; 36:449.
- Mahadevan U, Tremaine WJ, Johnson T, et al. Intravenous azathioprine in severe ulcerative colitis: a pilot study. Am J Gastroenterol 2000; 95:3463.
- Sandborn WJ, Tremaine WJ, Wolf DC, et al. 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.
- George J, Present DH, Pou R, et al. The long-term outcome of ulcerative colitis treated with 6-mercaptopurine. Am J Gastroenterol 1996; 91:1711.
- Vilien M, Dahlerup JF, Munck LK, et al. Randomized controlled azathioprine withdrawal after more than two years treatment in Crohn's disease: increased relapse rate the following year. Aliment Pharmacol Ther 2004; 19:1147.
- Lémann M, Mary JY, Colombel JF, et al. A randomized, double-blind, controlled withdrawal trial in Crohn's disease patients in long-term remission on azathioprine. Gastroenterology 2005; 128:1812.
- Treton X, Bouhnik Y, Mary JY, et al. Azathioprine withdrawal in patients with Crohn's disease maintained on prolonged remission: a high risk of relapse. Clin Gastroenterol Hepatol 2009; 7:80.
- Bouhnik Y, Lémann M, Mary JY, et al. Long-term follow-up of patients with Crohn's disease treated with azathioprine or 6-mercaptopurine. Lancet 1996; 347:215.
- 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.
- Kim PS, Zlatanic J, Korelitz BI, Gleim GW. Optimum duration of treatment with 6-mercaptopurine for Crohn's disease. Am J Gastroenterol 1999; 94:3254.
- Timmer A, McDonald JW, Macdonald JK. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2007; :CD000478.
- Ardizzone S, Maconi G, Sampietro GM, et al. Azathioprine and mesalamine for prevention of relapse after conservative surgery for Crohn's disease. Gastroenterology 2004; 127:730.
- Chaparro M, Ordás I, Cabré E, et al. Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients. Inflamm Bowel Dis 2013; 19:1404.
- Bowen DG, Selby WS. Use of 6-mercaptopurine in patients with inflammatory bowel disease previously intolerant of azathioprine. Dig Dis Sci 2000; 45:1810.
- 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.
- Lees CW, Maan AK, Hansoti B, et al. Tolerability and safety of mercaptopurine in azathioprine-intolerant patients with inflammatory bowel disease. Aliment Pharmacol Ther 2008; 27:220.
- 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.
- Kandiel A, Fraser AG, Korelitz BI, et al. Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine. Gut 2005; 54:1121.
- Khan N, Abbas AM, Lichtenstein GR, et al. Risk of lymphoma in patients with ulcerative colitis treated with thiopurines: a nationwide retrospective cohort study. Gastroenterology 2013; 145:1007.
- Disanti W, Rajapakse RO, Korelitz BI, et al. Incidence of neoplasms in patients who develop sustained leukopenia during or after treatment with 6-mercaptopurine for inflammatory bowel disease. Clin Gastroenterol Hepatol 2006; 4:1025.
- Lewis JD, Bilker WB, Brensinger C, et al. Inflammatory bowel disease is not associated with an increased risk of lymphoma. Gastroenterology 2001; 121:1080.
- Connell WR, Sheffield JP, Kamm MA, et al. Lower gastrointestinal malignancy in Crohn's disease. Gut 1994; 35:347.
- Greenstein AJ, Mullin GE, Strauchen JA, et al. Lymphoma in inflammatory bowel disease. Cancer 1992; 69:1119.
- Present DH, Meltzer SJ, Krumholz MP, et al. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med 1989; 111:641.
- Lewis JD, Schwartz JS, Lichtenstein GR. Azathioprine for maintenance of remission in Crohn's disease: benefits outweigh the risk of lymphoma. Gastroenterology 2000; 118:1018.
- Beaugerie L, Brousse N, Bouvier AM, et al. Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet 2009; 374:1617.
- Larvol L, Soule JC, Le Tourneau A. Reversible lymphoma in the setting of azathioprine therapy for Crohn's disease. N Engl J Med 1994; 331:883.
- Connell WR, Kamm MA, Dickson M, et al. Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet 1994; 343:1249.
- Li S, Borowitz MJ. Primary Epstein-Barr virus-associated Hodgkin disease of the ileum complicating Crohn disease. Arch Pathol Lab Med 2001; 125:424.
- Calaminici MR, Sheaff MT, Norton AJ, Feakins RM. Ileocaecal Epstein-Barr virus-positive lymphoproliferative disorder complicating Crohn's disease. Histopathology 1999; 35:388.
- Dayharsh GA, Loftus EV Jr, Sandborn WJ, et al. Epstein-Barr virus-positive lymphoma in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine. Gastroenterology 2002; 122:72.
- Mackey AC, Green L, Liang LC, et al. Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2007; 44:265.
- Kotlyar DS, Osterman MT, Diamond RH, et al. A systematic review of factors that contribute to hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2011; 9:36.
- Cuffari C, Théorêt Y, Latour S, Seidman G. 6-Mercaptopurine metabolism in Crohn's disease: correlation with efficacy and toxicity. Gut 1996; 39:401.
- Dubinsky MC, Lamothe S, Yang HY, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 2000; 118:705.
- Ardizzone S, Molteni P, Imbesi V, et al. Azathioprine in steroid-resistant and steroid-dependent ulcerative colitis. J Clin Gastroenterol 1997; 25:330.
- Tanis AA. Azathioprine in inflammatory bowel disease, a safe alternative? Mediators Inflamm 1998; 7:141.
- Shorey J, Schenker S, Suki WN, Combes B. Hepatotoxicity of mercaptopurine. Arch Intern Med 1968; 122:54.
- Dose in patients on allopurinol and 5-ASAs
- Split-dose administration
- TIMING OF RESPONSE
- DURATION OF TREATMENT AND TAPERING
- ADVERSE EFFECTS
- MONITORING FOR TOXICITY
- Laboratory testing
- Metabolite testing
- AZATHIOPRINE AND 6-MERCAPTOPURINE IN PREGNANCY
- SOCIETY GUIDELINE LINKS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS