Low-Dose Azathioprine in Combination with Allopurinol: The Past, Present and Future of This Useful Duo

Abstract

The inflammatory bowel diseases (IBD) are complex immune-mediated inflammatory diseases that are associated with significant morbidity around the world. As our understanding of IBD, and other immune-mediated inflammatory diseases, advances the number of therapeutic targets has increased which has rapidly driven the development and introduction of new therapies. While these new therapies have shown promise they come with the significant drawback of high costs. For many IBD patients around the world the cost of newer therapies is prohibitive which means treating clinicians often need to turn to optimising simpler, older, and inexpensive medications. The concept of optimising well established cheaper medications is not unique to the management of IBD as health systems all over the world look to reduce costs while simultaneously improving patient outcomes. Despite thiopurines being used in the management IBD for over 60 years, many clinicians are still hesitant to use them due to perceptions around limited efficacy and poor tolerance. One method identified to potentially increase utilisation of thiopurines involves the coadministration of allopurinol. In this review we will explore the history, pharmacology, recent studies and give recommendations for the utilisation of the usual duo of azathioprine combined with allopurinol.

Allopurinol Disrupts Purine Metabolism to Increase Damage in Experimental Colitis

“…Despite these observations, it is worth noting that the combination of allopurinol with azathioprine is a therapeutic option for patients who experience intolerance or side effects of azathioprine monotherapy, or for patients who cannot afford or do not have access to more recent biologic drugs [ 52 ]. This is attributed to the reduction in 6-methyl-mercaptopurine levels and the optimization of therapeutic 6-thiopurine production, which is enabled through inhibition of xanthine oxidase by allopurinol [ 53 ].…”

“…This is attributed to the reduction in 6-methyl-mercaptopurine levels and the optimization of therapeutic 6-thiopurine production, which is enabled through inhibition of xanthine oxidase by allopurinol [ 53 ]. However, drugs of the thiopurine class are increasingly sparingly used in developed countries given their failure to demonstrate equivalent effectiveness when compared to modern biologics, which have faster onset therapeutic action and less adverse drug reactions [ 52 , 54 ]. While the risk of cancer with combination allopurinol and thiopurine still needs to be addressed with further studies [ 53 ], historical addition of allopurinol to thiopurine therapy has been shown to improve disease activity scores, promoting clinical remission, and, as such, still plays a valuable role in the treatment of IBD when thiopurine administration is required [ 54 , 55 ].…”

Key factors associated with 6‐thioguanine and 6‐methylmercaptopurine nucleotide concentrations in children treated by thiopurine for acute leukaemia and inflammatory bowel disease

“…A 6MMP:6TGN ratio of >20, identified shunters, which may benefit from coadministration of allopurinol in children and thiopurine dose reduction to 25-33%. [36][37][38] T A B L E 3 6-methylmercaptopurine nucleotide concentrations* according to patients' characteristics and treatment. Hepatic and haematological biological adverse effects were more frequent in ALL than in IBD.…”

“…Low 6TGN concentrations were more frequently reported in IBD and high 6MMPN in ALL. A 6MMP:6TGN ratio of >20, identified shunters , which may benefit from coadministration of allopurinol in children and thiopurine dose reduction to 25–33% 36–38 …”

From niche to blockbuster: a greater role for allopurinol in maintenance treatment of acute lymphoblastic leukemia

“…A reasonable option originates from patients with inflammatory bowel disease (IBD). In IBD patients treated with azathioprine or MP who have an unfavorable ratio of TGN to methylated MP metabolites, the addition of the XO inhibitor allopurinol can lead to a reversal of the unfavorable metabolite ratio, resulting in increased therapeutic efficacy and less liver toxicity (8). Allopurinol may act through elevation of thioxanthine, an intermediate on the path of MP to TU, which was shown to inhibit TPMT.…”