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

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 (mu M) 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 mu M) 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 mu M), 5-aminosalicylate ( 3 - 14 mu M) and Ac-5-aminosalicylate ( 8 - 18 mu M) 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.