Advanced search
Publication Cover
Expert Opinion on Drug Safety Volume 7, 2008 - Issue 5
Submit an article Journal homepage
391
Views
28
CrossRef citations to date
0
Altmetric
Review

Thiopurine hepatotoxicity in inflammatory bowel disease: the role for adding allopurinol

Rupert WL Leong The University of New South Wales, Bankstown and Concord Hospitals, Gastroenterology and Liver Services, Sydney South West Area Health Service, Sydney, Australia; Concord Hospital, Ambulatory Care Endoscopy Unit, Level 1W, Hospital Road, Concord, NSW 2139, Australia +61 2 97676111; +61 2 97676767; [email protected]
, MBBS MD FRACP,
Richard B Gearry University of Otago, Christchurch Hospital and Department of Medicine, Department of Gastroenterology, Christchurch, New Zealand
, MBChB PhD FRACP &
Miles P Sparrow Box Hill Hospital and Monash University, Department of Gastroenterology, Melbourne, Australia
, MBBS FRACP
Pages 607-616 | Published online: 01 Sep 2008

Bibliography

  • Sandborn W, Sutherland L, Pearson D, et al. Azathioprine or 6-mercaptopurine for inducing remission of Crohn's disease. Cochrane Database Syst Rev 2000;CD000545
  • Pearson DC, May GR, Fick G, et al. Azathioprine for maintaining remission of Crohn's disease. Cochrane Database Syst Rev 2000;CD000067
  • 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(1):47-53
  • Timmer A, McDonald JWD, MacDonald JK. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2007;(1):CD000478
  • Holtmann MH, Krummenauer F, Claas C, et al. Long-term effectiveness of azathioprine in IBD beyond 4 years: a European multicenter study in 1176 patients. Dig Dis Sci 2006;51:1516-24
  • Ardizzone S, Maconi G, Sampietro GM, et al. Azathioprine and mesalamine for prevention of relapse after conservative surgery for Crohn's disease. Gastroenterology 2004;127:730-40
  • Hanauer SB, Korelitz BI, Rutgeerts P, et al. Postoperative maintenance of Crohn's disease remission with 6-mercaptopurine, mesalamine, or placebo: a 2-year trial. Gastroenterology 2004;127:723-9
  • Present DH, Korelitz BI, Wisch N, et al. Treatment of Crohn's disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med 1980;302:981-7
  • D'Haens G, Baert F, Van Assche G, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial. Lancet 2008;371(9613):660-7
  • Hommes D, Baert F, Van Assche G, et al. A randomized controlled trial evaluating the ideal medical management for Crohn's disease (CD): top-down vs. step-up strategies. Gastroenterology 2005;128:A577
  • Siegel CA, Sands BE. Review article: practical management of inflammatory bowel disease patients taking immunomodulators. Aliment Pharmacol Ther 2005;22:1-16
  • Gearry RB, Barclay ML, Burt MJ, et al. Thiopurine drug adverse effects in a population of New Zealand patients with inflammatory bowel disease. Pharmacoepidemiol Drug Saf 2004;13(8):563-7
  • 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(3):220-7
  • Colombel JF, Ferrari N, Debuysere H, et al. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy. Gastroenterology 2000;118(6):1025-30
  • Gearry RB, Richardson A, Frampton CM, et al. High incidence of Crohn's disease in Canterbury, New Zealand: results of an epidemiologic study. Inflamm Bowel Dis 2006;12(10):936-43
  • Hay JW, Hay AR. Inflammatory bowel disease: costs-of-illness. J Clin Gastroenterol 1992;14:309-17
  • Lichtenstein GR, Abreu MT, Cohen R, Tremaine W; American Gastroenterological Association. American Gastroenterological Association Institute medical position statement on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006;130(3):935-9
  • Elion GB, Hitchings GH, Vanderwerff H. Antagonists of nucleic acid derivatives. VI. Purines. J Biol Chem 1951;192(2):505-18
  • McGeown M, Douglas JF, Donaldson RA, et al. Ten-year results of renal transplantation with azathioprine and prednisolone as only immunosuppression. Lancet 1988;1:983-5
  • Bean RH. The treatment of chronic ulcerative colitis with 6-mercaptopurine. Med J Aust 1962;49:592-3
  • Brooke BN, Hoffmann DC, Swarbrick ET. Azathioprine for Crohn's disease. Lancet 1969;2:612-4
  • Chalmers AH. Studies on the mechanism of formation of 5-mercapto-1-methyl-4-nitroimidazole, a metabolite of the immunosuppressive drug azathioprine. Biochem Pharmacol 1974;23(13):1891-901
  • Sandborn WJ. Rational dosing of azathioprine and 6-mercaptopurine. Gut 2001;48(5):591-2
  • Swann PF, Waters TR, Moulton DC, et al. Role of postreplicative DNA mismatch repair in the cytotoxic action of thioguanine. Science 1996;273(5278):1109-11
  • Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol 1992;43:329-35
  • Tidd DM, Kim SC, Horakova K, et al. A delayed cytotoxic reaction for 6-mercaptopurine. Cancer Res 1972;32:317-22
  • 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;111:1133-45
  • 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;176:640-51
  • Neurath MF, Kiesslich R, Teichgraber U, et al. 6-thioguanosine diphosphate and triphosphate levels in red blood cells and response to azathioprine therapy in Crohn's disease. Clin Gastroenterol Hepatol 2005;3(10):1007-14
  • Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut 2002;50(4):485-9
  • Kirschner BS. Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease. Gastroenterology 1998;115(4):813-21
  • Teml A, Schaeffeler E, Herrlinger KR, et al. Thiopurine treatment in inflammatory bowel disease: clinical pharmacology and implication of pharmacogenetically guided dosing. Clin Pharmacokinet 2007;46(3):187-208
  • Hindorf U, Lindqvist M, Hildebrand H, et al. Adverse events leading to modification of therapy in a large cohort of patients with inflammatory bowel disease. Aliment Pharmacol Ther 2006;24(2):331-42
  • Bénichou C. Criteria of drug-induced liver disorders: report of an international consensus meeting. J Hepatol 1990;11:272-6
  • Bastida G, Nos P, Aguas M, et al. Incidence, risk factors and clinical course of thiopurine-induced liver injury in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2005;22(9):775-82
  • 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(8):641-9
  • 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(12):1561-5
  • Bowen DG, Selby WS. Use of 6-mercaptopurine in patients with inflammatory bowel disease previously intolerant of azathioprine. Dig Dis Sci 2000;45(9):1810-3
  • Domènech E, Nos P, Papo M, et al. 6-mercaptopurine in patients with inflammatory bowel disease and previous digestive intolerance of azathioprine. Scand J Gastroenterol 2005;40(1):52-5
  • Seidman EG. Clinical use and practical application of TPMT enzyme and 6-mercaptopurine metabolite monitoring in IBD. Rev Gastroenterol Disord 2003;3(Suppl 1):S30-8
  • Dubinsky MC, Lamothe S, Yang HY, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 2000;118(4):705-13
  • Dubinsky MC, Yang H, Hassard PV, et al. 6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease. Gastroenterology 2002;122(4):904-15
  • Mardini HE, Arnold GL. Utility of measuring 6-methylmercaptopurine and 6-thioguanine nucleotide levels in managing inflammatory bowel disease patients treated with 6-mercaptopurine in a clinical practice setting. J Clin Gastroenterol 2003;365:390-5
  • Shaye OA, Yadegari M, Abreu MT, et al. Hepatotoxicity of 6-mercaptopurine (6-MP) and Azathioprine (AZA) in adult IBD patients. Am J Gastroenterol 2007;102(11):2488-94
  • Tapner MJ, Jones BE, Wu WM, Farrell GC. Toxicity of low dose azathioprine and 6-mercaptopurine in rat hepatocytes. Roles of xanthine oxidase and mitochondrial injury. J Hepatol 2004;40(3):454-63
  • Collie-Duguid ES, Pritchard SC, Powrie RH, et al. The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. Pharmacogenetics 1999;9(1):37-42
  • Otterness D, Szumlanski C, Lennard L, et al. Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. Clin Pharmacol Ther 1997;62(1):60-73
  • Krynetski EY, Tai HL, Yates CR, et al. Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms. Pharmacogenetics 1996;6(4):279-90
  • Gardiner SJ, Gearry RB, Barclay ML, Begg EJ. Two cases of thiopurine methyltransferase (TPMT) deficiency – a lucky save and a near miss with azathioprine. Br J Clin Pharmacol 2006;62(4):473-6
  • Kaskas BA, Louis E, Hindorf U, et al. Safe treatment of thiopurine S-methyltransferase deficient Crohn's disease patients with azathioprine. Gut 2003;52(1):140-2
  • Gardiner SJ, Gearry RB, Begg EJ, et al. Thiopurine dose in intermediate and normal metabolizers of thiopurine methyltransferase may differ three-fold. Clin Gastroenterol Hepatol 2008;6(6):654-60
  • Schaeffeler E, Fischer C, Brockmeier D, et al. Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants. Pharmacogenetics 2004;14(7):407-17
  • Roberts RL, Gearry RB, Bland MV, et al. Trinucleotide repeat variants in the promoter of the thiopurine S-methyltransferase gene of patients exhibiting ultra-high enzyme activity. Pharmacogenet Genomics 2008;18(5):434-8
  • Ansari A, Hassan C, Duley J, et al. Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Aliment Pharmacol Ther 2002;16(10):1743-50
  • Sparrow MP, Hande SA, Friedman S, et al. Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine. Clin Gastroenterol Hepatol 2007;5(2):209-14
  • Sparrow MP, Hande SA, Friedman S, et al. Allopurinol safely and effectively optimizes thioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine. Aliment Pharmacol Ther 2005;22(5):441-6
  • Witte TN, Ginsberg AL. Use of allopurinol with low-dose 6-mercaptopurine in inflammatory bowel disease to achieve optimal active metabolite levels: a review of four cases and the literature. Can J Gastroenterol 2008;22(2):181-5
  • Ansari A, Elliott T, Baburajan B, et al. Long term outcome of using allopurinol co-therapy as a strategy for overcoming thiopurine hepatotoxicity in treating inflammatory bowel disease. Aliment Pharmacol Ther 2008 Jun 26. [Epub ahead of print]
  • Lennard L, Lilleyman JS. Individualizing therapy with 6-mercaptopurine and 6-thioguanine related to the thiopurine methyltransferase genetic polymorphism. Ther Drug Monit 1996;18(4):328-34
  • Gearry RB, Barclay ML. Azathioprine and 6-mercaptopurine pharmacogenetics and metabolite monitoring in inflammatory bowel disease. J Gastroenterol Hepatol 2005;20(8):1149-57
  • Osterman MT, Kundu R, Lichtenstein GR, Lewis JD. Association of 6-thioguanine nucleotide levels and inflammatory bowel disease activity: a meta-analysis. Gastroenterology 2006;130(4):1047-53
  • Goldenberg BA, Rawsthorne P, Bernstein CN. The utility of 6-thioguanine metabolite levels in managing patients with inflammatory bowel disease. Am J Gastroenterol 2004;99(9):1744-8
  • Belaiche J, Desager JP, Horsmans Y, Louis E. Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn disease. Scand J Gastroenterol 2001;36(1):71-6
  • Lowry PW, Franklin CL, Weaver AL, et al. Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease. Gut 2001;49(5):665-70
  • Wright S, Sanders DS, Lobo AJ, Lennard L. Clinical significance of azathioprine active metabolite concentrations in inflammatory bowel disease. Gut 2004;53(8):1123-8
  • Elion GB. The purine path to chemotherapy. Science 1989;244(4900):41-7
  • Borges F, Fernandes E, Roleira F. Progress towards the discovery of xanthine oxidase inhibitors. Curr Med Chem 2002;9(2):195-217
  • EBPG Expert Group on Renal Transplantation. European best practice guidelines for renal transplantation. Section IV. Long-term management of the transplant recipient. IV.9.2. Haematological complications. Leukopenia. Nephrol Dial Transplant 2002;17(Suppl 4):49
  • Chocair P, Duley J, Simmonds HA, et al. Low-dose allopurinol plus azathioprine/ cyclosporin/ prednisolone, a novel immunosuppressive regimen. Lancet 1993;342(8863):83-4
  • Chrzanowska M, Krzymanski M. Determination of 6-thioguanine and 6-methylmercaptopurine metabolites in renal transplantation recipients and patients with glomerulonephritis treated with azathioprine. Ther Drug Monit 1999;21(2):231-7
  • Wong DR, Derijks LJ, Den Dulk MO, et al. The role of xanthine oxidase in thiopurine metabolism: a case report. Ther Drug Monit 2007;29(6):845-8
  • Zimm S, Collins JM, O'Neill D, et al. Inhibition of first-pass metabolism in cancer chemotherapy: interaction of 6-mercaptopurine and allopurinol. Clin Pharmacol Ther 1983;34(6):810-7
  • Cummins D, Sekar M, Halil O, Banner N. Myelosuppression associated with azathioprine-allopurinol interaction after heart and lung transplantation. Transplantation 1996;61(11):1661-2

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Order Reprints Request Corporate Permissions

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

Request Academic Permissions

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.