Drug Insight: Pharmacology and toxicity of thiopurine therapy in patients with IBD

Nature Clinical Practice Gastroenterology and Hepatology

Volumn 4, Issue 12, 2007, Pages 686-694

  de Boer, Nanne K H ^a   van Bodegraven, Adriaan A ^a   Jharap, Bindia ^a   de Graaf, Peer ^a   Mulder, Chris J J ^a  

^a VU UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

6 MERCAPTOPURINE DERIVATIVE; ACETYLSALICYLIC ACID; ALLOPURINOL; AZATHIOPRINE; FUROSEMIDE; INFLIXIMAB; INOSINE DERIVATIVE; INOSINE TRIPHOSPHATE PYROPHOSPHATASE; MERCAPTOPURINE; MESALAZINE; METHOTREXATE; THIOPURINE METHYLTRANSFERASE; TIOGUANINE; UNCLASSIFIED DRUG;

ACUTE LYMPHOBLASTIC LEUKEMIA; ALLERGIC REACTION; ANTIINFLAMMATORY ACTIVITY; ARTHRALGIA; BONE MARROW APLASIA; BONE MARROW TOXICITY; CANCER RISK; CHROMOSOME 6; CLINICAL TRIAL; CROHN DISEASE; DOSE RESPONSE; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG ERUPTION; DRUG FEVER; DRUG HALF LIFE; DRUG MECHANISM; DRUG METABOLISM; DRUG POTENTIATION; DRUG SUBSTITUTION; DRUG WITHDRAWAL; ENTERITIS; ENZYME ACTIVITY; FLU LIKE SYNDROME; GASTROINTESTINAL SYMPTOM; GENETIC ASSOCIATION; HEPATITIS; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; LEUKEMIA; LEUKOPENIA; LIVER BIOPSY; LIVER FUNCTION TEST; LIVER HYPERPLASIA; LIVER TOXICITY; LIVER VENOOCCLUSIVE DISEASE; LOW DRUG DOSE; LYMPHOMA; MAINTENANCE DRUG DOSE; MALAISE; MYALGIA; PANCREAS DISEASE; PANCREATITIS; PANCYTOPENIA; PATIENT COMPLIANCE; PELIOSIS HEPATIS; PLASMA HALF LIFE; PREGNANCY OUTCOME; PRIORITY JOURNAL; REVIEW; SIDE EFFECT; SINGLE NUCLEOTIDE POLYMORPHISM; SKIN CANCER; THROMBOCYTOPENIA;

DRUG TOXICITY; HUMANS; INFLAMMATORY BOWEL DISEASES; METHYLTRANSFERASES; TREATMENT OUTCOME;

EID: 36749054030     PISSN: 17434378     EISSN: 17434386     Source Type: Journal    
DOI: 10.1038/ncpgasthep1000     Document Type: Review

References (92)

1. Sandborn W et al. Azathioprine or 6-mercaptopurine for inducing remission in Crohn's disease. Cochrane Database of Systematic Reviews 2000, Issue 2. Art 1. No.: CD000545.pub2. doi:10.1002/ 14651858.CD000545.pub2
2. Timmer A et al. (2007) Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database of Systematic Reviews 2007, Issue 1. Art No.: CD000478.pub2. doi:10.1002/14651858.CD000478.pub2
3. Pearson DC et al. Azathioprine for maintaining remission of Crohn's disease. Cochrane Database of Systematic Reviews 2000, Issue 2. Art. No.: CD000067.pub2. doi:10.1002/14651858.CD000067.pub2
4. Lichtenstein GR et al. (2006) American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 130: 940-987
5. de Jong DJ et al. (2003) Safety of thiopurines in the treatment of inflammatory bowel disease. Scand J Gastroenterol Suppl 239: 69-72
6. de Boer NK et al. (2006) 6-Thioguanine treatment in inflammatory bowel disease: A critical appraisal by a European 6-TG working party. Digestion 73: 25-31
7. Schwab M and Klotz U (2001) Pharmacokinetic considerations in the treatment of inflammatory bowel disease. Clin Pharmacokinet 40 723-751
8. Cuffari C et al. (2000) Enhanced bioavailability of azathioprine compared to 6-mercaptopurine therapy in inflammatory bowel disease: correlation with treatment efficacy. Aliment Pharmacol Ther 14 1009-1014
9. Lennard L (1992) The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol 43: 329-339
10. Neurath MF et al. (2005) 6-thioguanosine diphosphate and triphosphate levels in red blood cells and response to azathioprine therapy in Crohn's disease. Clin Gastroenterol Hapatol 3: 1007-1014
11. Tabloid® (oral thiogaunine) prescribing information (GlaxoSmithKline 2004) [http://us.gsk.com/products/assets/us_tabloid.pdf] (accessed 25 September 2007)
12. Lennard L et al. (11993) Is 6-thioguanine more appropriate than 6-mercaptopudne for children with acute lymphoblastic leukaemia? Br J Cancer 68: 186-190
13. Deibert P et al. (2003) High variation of tioguanine absorption in patients with chronic active Crohn's disease. Aliment Pharmacol Ther 18: 183-189
14. de Boer NK et al. (2007) Extended thiopurine metabolite assessment during 6-thioguanine therapy for immunomodulation in Crohn's disease. J Clin Pharmacol 47: 187-191
15. Pettersson B et al. (2002) Differences between children and adults in thiopurine methyltransferase activity and metabolite formation during thiopurine therapy: Possible role of concomitant methotrexate. Ther Drug Monit 24: 351-358
16. Weinshilboum RM and Sladek SL (1980) Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 32: 651-662
17. Tai HL et al. (1996) Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Am J Hum Genet 58: 694-702
18. Schwab M et al. (2001) Shortcoming in the diagnosis of TPMT deficiency in a patient with Crohn's disease using phenotyping only. Gastroenterology 121: 498-499
19. Marathias VM et al. (11999) 6-Thioguanine alters the structure and stability of duplex DNA and inhibits quadruplex DNA formation. Nucleic Acids Res 27: 2860-2867
20. Fairchild CR et al. (1986) Concurrent unilateral chromatid damage and DNA strand breakage in response to 6-thioguanine treatment. Biochem Pharmacol 35: 3533-3541
21. Somerville L et al. (2003) Structure and dynamics of thioguanine-modified duplex DNA. J Biol Chem 278: 1005-1011
22. Swann PF et al. (11996) Role of postreplicative DNA mismatch repair in the cytotoxic action of thioguanine. Science 273: 1109-1011
23. Lennard L (2002) TPMT in the treatment of Crohn's disease with azathioprine. Gut 51: 143-146
24. Dervieux T et al. (2001) Differing contribution of thiopurine methyltransferase to mercaptopurine versus thioguanine effects in human leukemic cells. Cancer Res 61: 5810-5816
25. Tidd DM et al. (1972) A delayed cytotoxic reaction for 6-mercaptopudne. Cancer Res 32: 317-322
26. Cuffed C et al. (2004) Peripheral blood mononuclear cell DNA 6-thioguanine metabolite levels correlate with decreased interferon-gamma production in patients with Crohn's disease on AZA therapy. Dig Dis Sci 49: 133-137
27. Thomas CW et al. (2005) Selective inhibition of inflammatory gene expression in activated T lymphocytes: A mechanism of immune suppression by thiopurines. J. Pharmacol Exp Ther 312: 537-545
28. + T lymphocytes. J Clin Invest 111: 1133-1145
29. Poppe D et al. (2006) Azathioprine suppresses ezrin-radixin-moesin-dependent T cell-APC conjugation through inhibition of Vav guanosine exchange activity on Rac proteins. J Immunol 176: 640-651
30. Quéméneur L et al. (2003) Differential control of cell cycle, proliferation, and survival of primary T lymphocytes by purine and pyrimidine nucleotides. J Immunol 170: 4986-4995
31. McGovern DP et al. (2002) Azathioprine intolerance in patients with IBD may be imidazole-related and is independent of TPMT activity. Gastroenterology 122: 838-839
32. Boulton-Jones JR et al. (2000) The use of 6-mercaptopurine in patients with inflammatory bowel disease after failure of azathioprine therapy. Aliment Pharmacol Ther 14: 1561-1565
33. Marinaki AM et al. (2004) Adverse drug reactions to azathioprine are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). Pharmacogenetics 14: 181-187
34. Zelinkova Z et al. (2006) Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression. Clin Gastroenterol Hepatol 4: 44-49
35. Sumi et al. (2002) Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency. Hum Genet 111: 360-367
36. Gearry RB et al. (2004) Lack of association between the ITPA 94C>A polymorphism and adverse effects from azathioprine. Pharmacogenetics 14, 779-781
37. Allorge D et al. (2005) ITPA genotyping test does not improve detection of Crohn's disease patients at risk of azathioprine/ 6-mercaptopurine induced myelosuppression. Gut 54: 565
38. de Boer NK et al. (2005) On tolerability and safety of a maintenance treatment with 6-thioguanine in azathioprine or 6-mercaptopurine intolerant IBD patients. World J Gastroenterol 11: 5540-5544
39. Herrlinger KIR et al. (2003) Remission maintenance by tioguanine in chronic active Crohn's disease. Aliment Pharmacol Ther 17 1459-1464
40. Present DH et al. (1989) 6-Mercaptopurine in the management of inflammatory bowel disease: Short-and long-term toxicity. Ann Inte Med 111: 641-649
41. Connell WR et al. (1993) Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut 34, 1081-10135
42. Dubinsky MC et al. (2000) Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 118: 705-713
43. Kaskas BA et al. (2003) Safe treatment of thiopurine S-methyltransferase deficient Crohn's disease patients with azathioprine. Gut 52: 140-142
44. Colombel JF et al. (2000) Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy. Gastroenterology 118: 1025-1030
45. Dewit O et al. (2002) Interaction between azathioprine and aminosalicylates: An in vivo study in patients with Crohn's disease. Aliment Pharmacol Ther 16: 79-85
46. Yin H et al. (2005) Effects of aminosalicylates on thiopurine S-methyltransferase activity: An ex vivo study in patients with inflammatory bowel disease. Aliment Pharmacol Ther 21: 1105-1109
47. Hande S et al. (2006) 5-aminosalicylate therapy is associated with higher 6-thioguanine levels in adults and children with inflammatory bowel disease in remission on 6-mercaptopurine or azathioprine. Inflamm Bowel Dis 12: 261-257
48. Lowry PW et al. (2001) Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine, or balsalazide. Gut 49: 656-664
49. Zimm S et al. (1983) Inhibition of first-pass metabolism in cancer chemotherapy: Interaction of 6-mercaptopurine and allopurinol. Clin Pharmacol Ther 34: 810-817
50. Sparrow MP et al. (2005) Alopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine. Aliment Pharmacol Ther 22: 441-446
51. Sparrow MP et al. (2007) Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine. Clin Gastroenterol Hepatol 5: 209-214
52. Herrlinger KR et al. (2004) Thioguanine-nucleotides do not predict efficacy of tioguanine in Crohn's disease. Aliment Pharmacol Ther 19: 1269-1276
53. Dubinsky MC et al. (2001) An open-label pilot study using thioguanine as a therapeutic alternative in Crohn's disease patients resistant to 6-mercaptopurine therapy. Inflamm Bowel Dis 7: 181-189
54. Dubinsky MC et al. (2003) 6-thioguanine can cause serious liver injury in inflammatory bowel disease patients. Gastroenterology 125: 298-303
55. de Boer NK et al. (2005) On the limitation of 6-tioguaninenucleotide monitoring during tioguanine treatment. Aliment Pharmacol Ther 22 447-451
56. McBride KL et al. (2000) Severe 6-thioguanine-induced marrow aplasia in a child with acute lymphoblastic leukemia and inherited thiopurine methyltransferase deficiency. J Pediatr Hematol Oncol 22: 441-445
57. Fraser AG et al. (2002) The efficacy of azathioprine for the treatment of inflammatory bowel disease: A 30 year review. Gut 50: 485-489
58. Schwab M et al. (2002) Azathioprine therapy and adverse drug reactions in patients with inflammatory bowel disease: Impact of thiopurine S-methyltransferase polymorphism. Pharmacogenetics 12: 429-436
59. Lee WM (2003) Drug-induced hepatotoxicity. N Engl J Med 349: 474-485
60. Dubinsky MC et al. (2002) 6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease. Gastroenterology 122: 904-915
61. Gilissen LP et al. (2004) Some cases demonstrating the clinical usefulness of therapeutic drug monitoring in thiopurine-treated inflammatory bowel disease patients. Eur J Gastroenterol Hepatol 16: 705-710
62. Goldenberg BA et al. (2004) The utility of 6-thioguanine metabolite levels in managing patients with inflammatory bowel disease. Am J Gastroenterol 99: 1744-1748
63. Wright S et al. (2004) Clinical significance of azathioprine active metabolite concentrations in inflammatory bowel disease. Gut 53: 1123-1128
64. Reshamwala PA et al. (2006) Nodular regenerative hyperplasia: Not all nodules are created equal. Hepatology 44: 7-14
65. Haboubi NY et al. (1988) Role of endothelial cell injury in the spectrum of azathioprine-induced liver disease after renal transplant: light microscopy and ultrastructural observations. Am J Gastroenterol 83: 256-261
66. Vernier-Massouille G et al. (2007) Nodular regenerative hyperplasia in patients with inflammatory bowel disease treated with azathioprine. Gut 56: 1404-1409
67. Seiderer J et al. (2006) Nodular regenerative hyperplasia: A reversible entity associated with azathioprine therapy. Eur J Gastroenterol Hepatol 18: 553-555
68. Seiderer J et al. (2005) A multicenter assessment of liver toxicity by MRI and biopsy in IBD patients on 6-thioguanine. J Hepatol 43: 303-309
69. Geller SA et al. (2004) Early hepatic nodular hyperplasia and submicroscopic fibrosis associated with 6-thioguanine therapy in inflammatory bowel disease. Am J Surg Pathol 28: 1204-1211
70. de Boer NK et al. (2006) Hepatotoxicity of long-term and low-dose 6-thioguanine in IBD patients. Gastroenterology 130: A202-A203
71. de Boer NK et al. (2005) Nodular regenerative hyperplasia and thiopurines: The case for level-dependent toxicity. Liver Transpl 11: 1300-1301
72. Breen DIP et al. (2005) Pharmacogenetic association with adverse drug reactions to azathioprine immunosuppressive therapy following liver transplantation. Liver Transpl 11: 826-833
73. Kandiel A et al. (2005) Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine. Gut 54: 1121-1125
74. O'Donovan P et al. (2005) Azathioprine and UVA light generate mutagenic oxidative DNA damage. Science 309: 1871-1874
75. Lewis JD et al. (2000) Azathioprine for maintenance of remission in Crohn's disease: Benefits outweigh the risk of lymphoma. Gastroenterology 118: 1018-1024
76. Alstead EM et al. (1990) Safety of azathioprine in pregnancy in inflammatory bowel disease. Gastroenterology 99: 443-446
77. Francella A et al. (2003) The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: A retrospective cohort study. Gastroenterology 124: 9-17
78. Nørgård B et al. (2007) Disease activity in pregnant women with Crohn's disease and birth outcomes: A regional danish cohort study. Am J Gastroenterol 102: 1947-1954
79. Saarikoski S and Seppädä M (1973) Immunosuppression during pregnancy: Transmission of azathioprine and its metabolites from the mother to the fetus. Am J Obstet Gynecol 115: 1100-1106
80. De Boer NK et al. (2006) Azathioprine use during pregnancy: unexpected intrauterine exposure to metabolites. Am J Gastroenterol 101: 1390-1392
81. Gardiner SJ et al. (2006) Exposure to thiopurine drugs through breast milk is low based on metabolite concentrations in mother-infant pairs. Br J Clin Pharmacol 62: 453-456
82. Sau A et al. (2007) Azathioprine and breastfeeding: Is it safe? BJOG 114: 498-501
83. de Boer NK et al. (2005) 6-Thioguanine for Crohn's disease during pregnancy: Thiopurine metabolite measurements in both mother and child. Scand J Gastroenterol 40: 1374-1377
84. Travis SP et al. (2006) European evidence based consensus on the diagnosis and management of Crohn's disease: Current management. Gut 65 (Suppl 1): I16-i35
85. Winter J et al. (2004) Cost-effectiveness of thiopurine methyltransferase genotype screening in patients about to commence azathioprine therapy for treatment of inflammatory bowel disease. Aliment Pharmacol Ther 20: 593-599
86. Dubinsky MC et al. (2005) A cost-effectiveness analysis of alternative disease management strategies in patients with Crohn's disease treated with azathioprine or 6-mercaptopurine. Am J Gastroenterol 100: 2239-2247
87. Sandborn WJ (2001) Rational dosing of azathioprine or 6-mercaptopurine. Gut 48: 591-592
88. Osterman MT et al. (2006) Association of 6-thioguanine nucleotide levels and inflammatory bowel disease activity: A meta-analysis. Gastroenterology 130: 1047-1053
89. Reinshagen M et al. (2007) 6-Thioguanine nucleotide-adapted azathioprine therapy does not lead to higher remission rates than standard therapy in chronic active Crohn's disease: Results from a randomized, controlled, open trial. Clin Chem 53: 1306-1314
90. Belaiche J et al. (2001) Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn disease. Scand J Gastroenterol 36: 71-76
91. Goldenberg BA et al. (2004) The utility of 6-thioguanine metabolite levels in managing patients with inflammatory bowel disease. Am J Gastroenterol 99: 1744-1748
92. Wusk B et al. (2004) Therapeutic drug monitoring of thiopurine drugs in patients with inflammatory bowel disease or autoimmune hepatitis. Eur J Gastroenterol Hepatol 16: 1407-1413