Introduc Tion and Outline of This Thesis

INTRODUCTION Inflammatory bowel diseases (IBD), comprising Crohn's disease, ulcerative colitis and IBD-unclassified, are chronic recurrent inflammatory disorders of the (large) intestine with a heterogeneous, but often disabling disease presentation. The prevalence of IBD is increasing worldwide and medical therapies are introduced earlier to improve health-related quality of life and postpone surgical interventions 1,2. This has led to the more extensive use of immunosuppressive therapies including biologicals and thiopurines. While the use of tioguanine was soon abandoned due to toxicity concerns 3 , over the years efficacy data on the use of azathioprine and mercaptopurine for the treatment of IBD has grown 4,5. However, due to side effects and ineffectiveness, related to unprofitable metabolism, thiopurine therapy often fails; up to 50% of patients discontinues treatment within 2 years 6. Increasing the knowledge on thiopurine metabolism may provide opportunities to further explore the therapeutic usefulness of thiopurines, which both from a patient's perspective and a pharmacoeconomic perspective is essential. both employees of Burroughs-Wellcome, focussing on the advent of drugs that inhibited cell growth without doing harm to the host cells. They discovered that purine bases are essential components of nucleic acids and vital for cell growth 7. Subsequently, they designed the purine antagonists diaminopurine and tioguanine that blocked the synthesis of original nucleic acids and inhibited cell growth 8. For the first time a successful treatment of leukaemia became available. Some years later Elion and colleagues also developed mercaptopurine, azathioprine, allopurinol, trimethoprim and acyclovir. Based on their research the important HIV drug azidothymidine was discovered. For their achievements in drug discovery Elion and Hitchings received the distinguished Nobel Prize, awarded in 1988. Although the thiopurines tioguanine and mercaptopurine were originally developed and registered for treating leukaemia, and azathioprine for preventing organ rejection in transplantation medicine, since 1962 these drugs have also been used for treating inflammatory mediated diseases including IBD 9-11. It soon became evident that these thiopurines have a small therapeutic window and that their use is not without risk. Both efficacy and toxicity of these drugs are dependent on the extent to which pharmacologically active and toxic metabolites are produced. On the one hand azathioprine is converted, via the formation of mercaptopurine and other intermediates, into the pharmacologically active (but also cytotoxic) 6-thioguanine nucleotides (6-TGN). These 6-TGN are associated with therapeutic response 12,13. On the other hand, 6-methylmercaptopurine ribonucleotides (6-MMP) are formed and related to the occurrence of adverse events …