The fate of thiopurine metabolites after switching to low-dose thiopurine with allopurinol or thioguanine in IBD patients: A retrospective analysis

Aims: Shunting (hypermethylating) thiopurine metabolism, characterized by excessive 6-MMPR production and (sub)therapeutic 6-TGN levels, poses a significant challenge in the treatment of inflammatory bowel disease (IBD). This study evaluates the metabolic outcomes of switching to low-dose thiopurine with allopurinol (LDTA) or thioguanine (TG) in IBD patients with shunting metabolism. Methods: This retrospective study analysed demographic data, thiopurine metabolite profiles, and adverse event rates in shunting IBD patients before and after switching to LDTA or TG therapy. Metabolite variability was assessed by examining alterations in 6-MMPR and 6-TGN levels and their correlation before and after therapy switch. Results: Both therapies significantly reduced toxic 6-MMPR levels, with 100% of patients achieving non-toxic levels (6-MMPR-level below 7000 pmol/8 × 10E8 RBC) post-therapy. For TG, 93% of patients attained non-toxic 6-TGN levels (6-TGN < 1000 pmol/8 × 10E8 RBC). In contrast, LDTA showed greater variability in 6-TGN outcomes, with 50% of patients reaching therapeutic levels, 31% remaining subtherapeutic, and 19% within toxic range. The slope for LDTA was significantly positive (1.044, R² = 0.4515, P = 0.004), reflecting proportional increases in 6-TGN levels. Conclusions: Switching to LDTA or TG therapy in shunting IBD patients resulted in favourable alterations in thiopurine metabolism. However, LDTA appears to have a slightly less favourable metabolite profile, with some residual 6-MMPR formation and fewer patients achieving normal 6-TGN levels compared to TG. Given the challenges associated with achieving optimal thiopurine metabolite levels with LDTA and the need for closer monitoring of 6-TGN levels, TG appears a more suitable option for thiopurine shunting IBD patients.