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RESEARCH PRODUCT

Understanding the delayed onset of action of azathioprine in IBD: are we there yet?

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In this issue of Gut , Ben-Horin et al propose an innovative explanation for the well known phenomenon of the delayed onset of action of thiopurines ( see page 396 ). They thereby contribute to an improved insight into the exact mode of action of the classic immunosuppressive drug azathioprine.1 Developing azathioprine as an innovative immunosuppressive drug in 1957, Gertrude Elion and George Hitchings laid the basis for the currently utilised concept of steroid-sparing treatment strategies in inflammatory bowel diseases (IBD).2 With regard to the evidence-based immunosuppressive capacity and clinical efficacy of azathioprine in the context of IBD as well as considering the proven long-term safety of this drug, which has been confirmed in numerous trials, the primary obstacle to the successful use of azathioprine in the treatment of acute flares of IBD is its delayed onset of action.3 4 As it often takes several months after initiating treatment with azathioprine until the first clinical effects can be monitored, it is sometimes impossible to avoid completely the parallel use of fast-acting steroids in order to control acute flares of intestinal inflammation.3 5 However, do we really have to accept this shortcoming of our old ally azathioprine in the induction of remission in IBD, or might there today, five decades after the birth of azathioprine, exist modern tools of biochemical and medical science which possibly can enable us to overcome these limitations by a rational design of innovative azathioprine-based immunosuppressive formulas? Thinking about this point, subsequently the question arises of what exactly should such a possible biochemical modification of azathioprine look like, in order to speed up its immunosuppressive capacity, and this would then automatically lead to the fundamental issue in this context—that is, do we really understand the detailed molecular mechanism of azathioprine and its metabolites which are …