Effects of aminosalicylates on thiopurine S-methyltransferase activity: an ex vivo study in patients with inflammatory bowel disease

Summary Background : Based on in vitro experiments using recombinant human thiopurine S-methyltransferase this enzyme is inhibited by sulfasalazine (sulphasalazine) and 5-aminosalicylate. Thus, during treatment with azathioprine or mercaptopurine, both metabolized by thiopurine S-methyltransferase,... Full description

Summary Background : Based on in vitro experiments using recombinant human thiopurine S-methyltransferase this enzyme is inhibited by sulfasalazine (sulphasalazine) and 5-aminosalicylate. Thus, during treatment with azathioprine or mercaptopurine, both metabolized by thiopurine S-methyltransferase, sulfasalazine or 5-aminosalicylate could modify the action of azathioprine/mercaptopurine. Aims : To examine whether this interaction is effective under ex vivo conditions. Methods : In 18 azathioprine-free patients and in 12 patients on azathioprine the inhibitory potential of sulfasalazine, 5-aminosalicylate and its metabolite (Ac-5-aminosalicylate) was assessed by ex vivo measurement of thiopurine S-methyltransferase in red blood cells. Results : According to concentration response curves mean IC50 values (μm) for sulfasalazine, 5-aminosalicylate and Ac-5-aminosalicylate have been calculated in three groups of azathioprine-free patients and variable basal levels of thiopurine S-methyltransferase activity (very high, normal and intermediate). In all three groups sulfasalazine was the strongest inhibitor (IC50: 9–17 μm) if compared with 5-aminosalicylate (129–236) and Ac-5-aminosalicylate (58–74). In patients on azathioprine similar IC50 values have been calculated. Conclusions : Comparing human plasma concentrations of sulfasalazine (15–77 μm), 5-aminosalicylate (3–14 μm) and Ac-5-aminosalicylate (8–18 μm) with the IC50 values one can assume that only sulfasalazine would have the potential to inhibit thiopurine S-methyltransferase in vivo. However, the therapeutic impact should be proved by clinical studies.