Azathioprine in inflammatory bowel disease: improved molecular insights and resulting clinical implications

References

• Glickmann RM. Inflammatory bowel disease.In: Ulcerative Colitis and Crohn’s disease. Fauci AS, Braunwald E, Isselbacher KJ et al. (Eds). McGraw–Hill, NY, USA, 1969–1974 (1991).
   Google Scholar
• Buhner S, Buning C, Genschel J et al. Genetic basis for increased intestinal permeability in families with Crohn’s disease: role of CARD15 3020insC mutation? Gut55, 342–347 (2006).
   PubMed Web of Science ®Google Scholar
• Hugot JP. CARD15/NOD2 mutations in Crohn’s disease. Ann. NY Acad. Sci.1072, 9–18 (2006).
   PubMed Web of Science ®Google Scholar
• Koutroubakis I, Manousos ON, Meuwissen SG et al. Environmental risk factors in inflammatory bowel disease. Hepatogastroenterology43, 381–393 (1996).
   PubMedGoogle Scholar
• Neurath MF, Schurmann G. Immunopathogenesis of inflammatory bowel diseases. Chirurg71, 30–40 (2000).
   PubMed Web of Science ®Google Scholar
• Strober W, Fuss I, Mannon P. The fundamental basis of inflammatory bowel disease. J. Clin. Invest.117, 514–521 (2007).
   PubMed Web of Science ®Google Scholar
• Carter MJ, Lobo AJ, Travis SP. Guidelines for the management of inflammatory bowel disease in adults. Gut53(Suppl. 5), V1–V16 (2004).
   PubMed Web of Science ®Google Scholar
• Targan SR, Deem RL, Liu M et al. Definition of a lamina propria T cell responsive state. Enhanced cytokine responsiveness of T cells stimulated through the CD2 pathway. J. Immunol.154, 664–675 (1995).
   PubMed Web of Science ®Google Scholar
• Allez M, Mayer L. Regulatory T cells: peace keepers in the gut. Inflamm. Bowel Dis.10, 666–676 (2004).
   PubMed Web of Science ®Google Scholar
• Braunstein J, Qiao L, Autschbach F et al. T cells of the human intestinal lamina propria are high producers of interleukin-10. Gut41, 215–220 (1997).
   PubMed Web of Science ®Google Scholar
• Neurath MF, Finotto S, Fuss I et al. Regulation of T-cell apoptosis in inflammatory bowel disease: to die or not to die, that is the mucosal question. Trends Immunol.22, 21–26 (2001).
   PubMed Web of Science ®Google Scholar
• Faubion WA Jr, Loftus EV Jr, Harmsen WS et al. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology121, 255–260 (2001).
   PubMed Web of Science ®Google Scholar
• Nguyen GC, Harris ML, Dassopoulos T. Insights in immunomodulatory therapies for ulcerative colitis and Crohn’s disease. Curr. Gastroenterol. Rep.8, 499–505 (2006).
   PubMedGoogle Scholar
• Sandborn WJ. Azathioprine: state of the art in inflammatory bowel disease. Scand. J. Gastroenterol.225, 92–99 (1998).
   Google Scholar
• Bean RH. The treatment of chronic ulcerative colitis with 6-mercaptopurine. Med. J. Aust.49(2), 592–593 (1962).
   PubMed Web of Science ®Google Scholar
• Ewe K, Press AG, Singe CC et al. Azathioprine combined with prednisolone or monotherapy with prednisolone in active Crohn’s disease. Gastroenterology105, 367–372 (1993).
   PubMed Web of Science ®Google Scholar
• Hawthorne AB, Logan RF, Hawkey CJ et al. Randomised controlled trial of azathioprine withdrawal in ulcerative colitis. BMJ305, 20–22 (1992).
   PubMed Web of Science ®Google Scholar
• Kirk AP, Lennard-Jones JE. Controlled trial of azathioprine in chronic ulcerative colitis. Br. Med. J. (Clin. Res. Ed.)284, 1291–1292 (1982).
   PubMed Web of Science ®Google Scholar
• O’Donoghue DP, Dawson A, Powell-Tuck J et al. Double-blind withdrawal trial of azathioprine as maintenance treatment for Crohn’s disease. Lancet2, 955–957 (1978).
   PubMed Web of Science ®Google Scholar
• Pearson DC, May GR, Fick GH et al. Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. Ann. Intern. Med.123, 132–142 (1995).
   PubMed Web of Science ®Google Scholar
• Sandborn W, Sutherland L, Pearson D et al. Azathioprine or 6-mercaptopurine for inducing remission of Crohn’s disease. Cochrane Database Syst. Rev. CD000545 (2000).
   Google Scholar
• Tanis AA. Azathioprine in inflammatory bowel disease, a safe alternative? >Mediators Inflamm.7, 141–144 (1998).
   PubMed Web of Science ®Google Scholar
• van Hogezand RA. Medical management of patients with difficult-to-treat inflammatory bowel disease. Neth. J. Med.45, 55–59 (1994).
   PubMed Web of Science ®Google Scholar
• Holtmann MH, Neurath MF. From immunogenic mechanisms to novel therapeutic approaches in inflammatory bowel disease. Adv. Exp. Med. Biol.579, 227–242 (2006).
   PubMed Web of Science ®Google Scholar
• Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet369, 1641–1657 (2007).
   PubMed Web of Science ®Google Scholar
• Sandborn WJ, Hanauer S, Loftus EV Jr et al. An open-label study of the human anti-TNF monoclonal antibody adalimumab in subjects with prior loss of response or intolerance to infliximab for Crohn’s disease. Am. J. Gastroenterol.99, 1984–1989 (2004).
   PubMed Web of Science ®Google Scholar
• Targan SR, Hanauer SB, van Deventer SJ et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn’s disease.Crohn’s Disease cA2 Study Group. N. Engl. J. Med.337, 1029–1035 (1997).
   PubMed Web of Science ®Google Scholar
• Atreya R, Mudter J, Finotto S et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo. Nat. Med.6, 583–588 (2000).
   PubMed Web of Science ®Google Scholar
• Ito H, Takazoe M, Fukuda Y et al. A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn’s disease. Gastroenterology126, 989–996 (2004).
   PubMed Web of Science ®Google Scholar
• Burakoff R, Barish CF, Riff D et al. A Phase 1/2A trial of STA 5326, an oral interleukin-12/23 inhibitor, in patients with active moderate to severe Crohn’s disease. Inflamm. Bowel Dis.12, 558–565 (2006).
   PubMed Web of Science ®Google Scholar
• Mannon PJ, Fuss IJ, Mayer L et al. Anti-interleukin-12 antibody for active Crohn’s disease. N. Engl. J. Med.351, 2069–2079 (2004).
   PubMed Web of Science ®Google Scholar
• Ghosh S, Goldin E, Gordon FH et al. Natalizumab for active Crohn’s disease. N. Engl. J. Med.348, 24–32 (2003).
   PubMed Web of Science ®Google Scholar
• Nakamura K, Honda K, Mizutani T et al. Novel strategies for the treatment of inflammatory bowel disease: selective inhibition of cytokines and adhesion molecules. World J. Gastroenterol.12, 4628–4635 (2006).
   PubMed Web of Science ®Google Scholar
• Vermeire S, Noman M, Van Assche G et al. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease. Gut56, 1226–1231 (2007).
   PubMed Web of Science ®Google Scholar
• Lemann M, Mary JY, Duclos B et al. Infliximab plus azathioprine for steroid-dependent Crohn’s disease patients: a randomized placebo-controlled trial. Gastroenterology130, 1054–1061 (2006).
   PubMed Web of Science ®Google Scholar
• Hanauer SB. Risks and benefits of combining immunosuppressives and biological agents in inflammatory bowel disease: is the synergy worth the risk? Gut56, 1181–1183 (2007).
   PubMed Web of Science ®Google Scholar
• 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.44, 265–267 (2007).
   PubMed Web of Science ®Google Scholar
• 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.176, 640–651 (2006).
   PubMed Web of Science ®Google Scholar
• 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.111, 1133–1145 (2003).
   PubMed Web of Science ®Google Scholar
• Mudter J, Neurath MF. Apoptosis of T cells and the control of inflammatory bowel disease: therapeutic implications. Gut56, 293–303 (2007).
   PubMed Web of Science ®Google Scholar
• Boirivant M, Marini M, Di Felice G et al. Lamina propria T cells in Crohn’s disease and other gastrointestinal inflammation show defective CD2 pathway-induced apoptosis. Gastroenterology116, 557–565 (1999).
   PubMed Web of Science ®Google Scholar
• Ina K, Itoh J, Fukushima K et al. Resistance of Crohn’s disease T cells to multiple apoptotic signals is associated with a Bcl-2/Bax mucosal imbalance. J. Immunol.163, 1081–1090 (1999).
   PubMed Web of Science ®Google Scholar
• Ito H, Hirotani T, Yamamoto M et al. Anti-IL-6 receptor monoclonal antibody inhibits leukocyte recruitment and promotes T-cell apoptosis in a murine model of Crohn’s disease. J. Gastroenterol.37(Suppl. 14), 56–61 (2002).
   PubMed Web of Science ®Google Scholar
• Fuss IJ, Marth T, Neurath MF et al. Anti-interleukin 12 treatment regulates apoptosis of Th1 T cells in experimental colitis in mice. Gastroenterology117, 1078–1088 (1999).
   PubMed Web of Science ®Google Scholar
• Van den Brande JM, Koehler TC, Zelinkova Z et al. Prediction of antitumour necrosis factor clinical efficacy by real-time visualisation of apoptosis in patients with Crohn’s disease. Gut56, 509–517 (2007).
   PubMed Web of Science ®Google Scholar
• Elion GB. The George Hitchings and Gertrude Elion Lecture.The pharmacology of azathioprine. Ann. NY Acad. Sci.685, 400–407 (1993).
   PubMed Web of Science ®Google Scholar
• Bohon J, de los Santos CR. Structural effect of the anticancer agent 6-thioguanine on duplex DNA. Nucleic Acids Res.31, 1331–1338 (2003).
   PubMed Web of Science ®Google Scholar
• Somerville L, Krynetski EY, Krynetskaia NF et al. Structure and dynamics of thioguanine-modified duplex DNA. J. Biol. Chem.278, 1005–1011 (2003).
   PubMed Web of Science ®Google Scholar
• Karran P. Thiopurines, DNA damage, DNA repair and therapy-related cancer. Br. Med. Bull.79–80, 153–170 (2006).
   PubMed Web of Science ®Google Scholar
• Maltzman JS, Koretzky GA. Azathioprine: old drug, new actions. J. Clin. Invest.111, 1122–1124 (2003).
   PubMed Web of Science ®Google Scholar
• Dayton JS, Turka LA, Thompson CB et al. Comparison of the effects of mizoribine with those of azathioprine, 6-mercaptopurine, and mycophenolic acid on T lymphocyte proliferation and purine ribonucleotide metabolism. Mol. Pharmacol.41, 671–676 (1992).
   PubMed Web of Science ®Google Scholar
• Quemeneur L, Gerland LM, Flacher M et al. Differential control of cell cycle, proliferation, and survival of primary T lymphocytes by purine and pyrimidine nucleotides. J. Immunol.170, 4986–4995 (2003).
   PubMed Web of Science ®Google Scholar
• Thomas CW, Myhre GM, Tschumper R et al. Selective inhibition of inflammatory gene expression in activated T lymphocytes: a mechanism of immune suppression by thiopurines. J. Pharmacol. Exp. Ther.312, 537–545 (2005).
   PubMed Web of Science ®Google Scholar
• 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.3, 1007–1014 (2005).
   PubMed Web of Science ®Google Scholar
• Cantrell D. Lymphocyte signalling: a coordinating role for Vav? Curr.Biol.8, R535–R538 (1998).
   PubMedGoogle Scholar
• Bustelo XR. Vav proteins, adaptors and cell signaling. Oncogene20, 6372–6381 (2001).
   PubMed Web of Science ®Google Scholar
• Khoshnan A, Tindell C, Laux I et al. The NF-κB cascade is important in Bcl-xL expression and for the anti-apoptotic effects of the CD28 receptor in primary human CD4+ lymphocytes. J. Immunol.165, 1743–1754 (2000).
   PubMed Web of Science ®Google Scholar
• Cantrell DA. GTPases and T cell activation. Immunol. Rev.192, 122–130 (2003).
   PubMed Web of Science ®Google Scholar
• Crespo P, Schuebel KE, Ostrom AA et al. Phosphotyrosine-dependent activation of Rac-1 GDP/GTP exchange by the Vav proto-oncogene product. Nature385, 169–172 (1997).
   PubMed Web of Science ®Google Scholar
• Darnell JE Jr. STATs and gene regulation. Science277, 1630–1635 (1997).
   PubMed Web of Science ®Google Scholar
• Fanger GR, Johnson NL, Johnson GL. MEK kinases are regulated by EGF and selectively interact with Rac/Cdc42. Embo J.16, 4961–4972 (1997).
   PubMed Web of Science ®Google Scholar
• Grad JM, Zeng XR, Boise LH. Regulation of Bcl-xL: a little bit of this and a little bit of STAT. Curr. Opin. Oncol.12, 543–549 (2000).
   PubMed Web of Science ®Google Scholar
• Bretscher A. Regulation of cortical structure by the ezrin–radixin–moesin protein family. Curr. Opin. Cell. Biol.11, 109–116 (1999).
   PubMed Web of Science ®Google Scholar
• Faure S, Salazar-Fontana LI, Semichon M et al. ERM proteins regulate cytoskeleton relaxation promoting T cell-APC conjugation. Nat. Immunol.5, 272–279 (2004).
   PubMed Web of Science ®Google Scholar
• 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.51, 1516–1524 (2006).
   PubMed Web of Science ®Google Scholar
• 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. Gastroenterology122, 904–915 (2002).
   PubMed Web of Science ®Google Scholar
• Stocco G, Martelossi S, Decorti G et al. Thiopurine-S-methyltransferase genotype and the response to azathioprine in inflammatory bowel disease. Aliment. Pharmacol. Ther.26, 1083–1084 (2007).
   PubMed Web of Science ®Google Scholar
• Winter JW, Gaffney D, Shapiro D et al. Assessment of thiopurine methyltransferase enzyme activity is superior to genotype in predicting myelosuppression following azathioprine therapy in patients with inflammatory bowel disease. Aliment. Pharmacol. Ther.25, 1069–1077 (2007).
   PubMed Web of Science ®Google Scholar
• Lamers CB, Griffioen G, van Hogezand RA et al. Azathioprine: an update on clinical efficacy and safety in inflammatory bowel disease. Scand. J. Gastroenterol.230(Suppl.), 111–115 (1999).
   Google Scholar
• Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut50, 485–489 (2002).
   PubMed Web of Science ®Google Scholar
• 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.111, 641–649 (1989).
   PubMed Web of Science ®Google Scholar
• Chang FW, Reinhart S, Fraser NM. Effect of 30% sodium sulfacetamide on corneal sensitivity. Am. J. Optom. Physiol. Opt.61, 318–320 (1984).
   PubMedGoogle Scholar
• Kinlen LJ. Incidence of cancer in rheumatoid arthritis and other disorders after immunosuppressive treatment. Am. J. Med.78, 44–49 (1985).
   PubMed Web of Science ®Google Scholar
• Opelz G, Henderson R. Incidence of non-Hodgkin lymphoma in kidney and heart transplant recipients. Lancet342, 1514–1516 (1993).
   PubMed Web of Science ®Google Scholar
• Silman AJ, Petrie J, Hazleman B et al. Lymphoproliferative cancer and other malignancy in patients with rheumatoid arthritis treated with azathioprine: a 20 year follow up study. Ann. Rheum. Dis.47, 988–992 (1988).
   PubMed Web of Science ®Google Scholar
• Garnier JL, Lebranchu Y, Dantal J et al. Hodgkin’s disease after transplantation. Transplantation61, 71–76 (1996).
   PubMed Web of Science ®Google Scholar
• Kwon JH, Farrell RJ. The risk of lymphoma in the treatment of inflammatory bowel disease with immunosuppressive agents. Crit. Rev. Oncol. Hematol.56, 169–178 (2005).
   PubMed Web of Science ®Google Scholar
• Lewis JD, Schwartz JS, Lichtenstein GR. Azathioprine for maintenance of remission in Crohn’s disease: benefits outweigh the risk of lymphoma. Gastroenterology118, 1018–1024 (2000).
   PubMed Web of Science ®Google Scholar
• de Jong DJ, Derijks LJ, Naber AH et al. Safety of thiopurines in the treatment of inflammatory bowel disease. Scand. J. Gastroenterol.239(Suppl.) 69–72 (2003).
   Google Scholar
• Osterman MT, Kundu R, Lichtenstein GR et al. Association of 6-thioguanine nucleotide levels and inflammatory bowel disease activity: a meta-analysis. Gastroenterology130, 1047–1053 (2006).
   PubMed Web of Science ®Google Scholar
• Teml A, Schaeffeler E, Herrlinger KR et al. Thiopurine treatment in inflammatory bowel disease: clinical pharmacology and implication of pharmacogenetically guided dosing. Clin. Pharmacokinet.46, 187–208 (2007).
   PubMed Web of Science ®Google Scholar
• Dilger K, Schaeffeler E, Lukas M et al. Monitoring of thiopurine methyltransferase activity in postsurgical patients with Crohn’s disease during 1 year of treatment with azathioprine or mesalazine. Ther. Drug Monit.29, 1–5 (2007).
   PubMed Web of Science ®Google Scholar
• Lennard L, Lilleyman JS, Van Loon J et al. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet336, 225–229 (1990).
   PubMed Web of Science ®Google Scholar
• Schaeffeler E, Eichelbaum M, Reinisch W et al. Three novel thiopurine S-methyltransferase allelic variants (TPMT*20, *21, *22) – association with decreased enzyme function. Hum. Mutat.27, 976– (2006).
   PubMedGoogle Scholar
• Lennard L. TPMT in the treatment of Crohn’s disease with azathioprine. Gut51, 143–146 (2002).
   PubMed Web of Science ®Google Scholar
• Szumlanski CL, Weinshilboum RM. Sulphasalazine inhibition of thiopurine methyltransferase: possible mechanism for interaction with 6-mercaptopurine and azathioprine. Br. J. Clin. Pharmacol.39, 456–459 (1995).
   PubMed Web of Science ®Google Scholar
• Xin HW, Fischer C, Schwab M et al. Thiopurine S-methyltransferase as a target for drug interactions. Eur. J. Clin. Pharmacol.61,395–398 (2005).
   Google Scholar
• Marinaki AM, Duley JA, Arenas M et al. Mutation in the ITPA gene predicts intolerance to azathioprine. Nucleosides Nucleotides Nucleic Acids23, 1393–1397 (2004).
   PubMed Web of Science ®Google Scholar
• 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.13, 57–64 (2007).
   PubMed Web of Science ®Google Scholar
• Shipkova M, Lorenz K, Oellerich M et al. Measurement of erythrocyte inosine triphosphate pyrophosphohydrolase (ITPA) activity by HPLC and correlation of ITPA genotype-phenotype in a Caucasian population. Clin. Chem.52, 240–247 (2006).
   PubMed Web of Science ®Google Scholar
• Eklund BI, Moberg M, Bergquist J et al. Divergent activities of human glutathione transferases in the bioactivation of azathioprine. Mol. Pharmacol.70, 747–754 (2006).
   PubMed Web of Science ®Google Scholar
• Hobara N, Watanabe A. Impaired metabolism of azathioprine in carbon tetrachloride-injured rats. Hepatogastroenterology28, 192–194 (1981).
   PubMedGoogle Scholar
• Herrlinger KR, Kreisel W, Schwab M et al. 6-thioguanine – efficacy and safety in chronic active Crohn’s disease. Aliment. Pharmacol. Ther.17, 503–508 (2003).
   PubMed Web of Science ®Google Scholar
• Palmieri O, Latiano A, Bossa F et al. Sequential evaluation of thiopurine methyltransferase, inosine triphosphate pyrophosphatase, and HPRT1 genes polymorphisms to explain thiopurines’ toxicity and efficacy. Aliment. Pharmacol. Ther.26, 737–745 (2007).
   PubMed Web of Science ®Google Scholar
• 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. Gastroenterology118, 1025–1030 (2000).
   PubMed Web of Science ®Google Scholar
• Winter J, Walker A, Shapiro D et al. 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 (2004).
   PubMed Web of Science ®Google Scholar
• Ansari A, Hassan C, Duley J et al. Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Aliment. Pharmacol. Ther.16, 1743–1750 (2002).
   PubMed Web of Science ®Google Scholar
• Campbell S, Kingstone K, Ghosh S. Relevance of thiopurine methyltransferase activity in inflammatory bowel disease patients maintained on low-dose azathioprine. Aliment. Pharmacol. Ther.16, 389–398 (2002).
   PubMed Web of Science ®Google Scholar
• Cuffari C, Dassopoulos T, Turnbough L et al. Thiopurine methyltransferase activity influences clinical response to azathioprine in inflammatory bowel disease. Clin. Gastroenterol. Hepatol.2, 410–417 (2004).
   PubMed Web of Science ®Google Scholar
• Reuther LO, Sonne J, Larsen NE et al. Pharmacological monitoring of azathioprine therapy. Scand. J. Gastroenterol.38, 972–977 (2003).
   PubMed Web of Science ®Google Scholar
• Cuffari C, Theoret Y, Latour S et al. 6-Mercaptopurine metabolism in Crohn’s disease: correlation with efficacy and toxicity. Gut39, 401–406 (1996).
   PubMed Web of Science ®Google Scholar
• Wusk B, Kullak-Ublick GA, Rammert C et al. Therapeutic drug monitoring of thiopurine drugs in patients with inflammatory bowel disease or autoimmune hepatitis. Eur. J. Gastroenterol. Hepatol.16, 1407–1413 (2004).
   PubMed Web of Science ®Google Scholar
• Herrlinger KR, Fellermann K, Fischer C et al. Thioguanine-nucleotides do not predict efficacy of tioguanine in Crohn’s disease. Aliment. Pharmacol. Ther.19, 1269–1276 (2004).
   PubMed Web of Science ®Google Scholar
• Lowry PW, Franklin CL, Weaver AL et al. Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease. Gut49, 665–670 (2001).
   PubMed Web of Science ®Google Scholar
• Cuffari C, Hunt S, Bayless T. Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease. Gut48, 642–646 (2001).
   PubMed Web of Science ®Google Scholar