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

Abstract

SUMMARYBackground: 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.

Identification of Patients With Variants in TPMT and Dose Reduction Reduces Hematologic Events During Thiopurine Treatment of Inflammatory Bowel Disease

“…sulfasalazine and 5-aminosalicylates are also implicated in the development of leucopenia. 29,30 Besides we show that baseline biologics use is linked to hematological ADR development. These non-genetic factors should be taken into consideration before thiopurine initiation as they might interfere with the genotype-guided dosing.…”

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…Therefore, measurement of TPMT activity may usually be more clinically relevant, except in the case of a recent blood transfusion, which may result in incorrect phenotype assignment. An argument that is often given in support of genotyping is that TPMT activity is inhibited by salicylates (mainly sulfasalazine) (Szumlanski and Weinshilboum, 1995;Lewis et al, 1997;Xin et al, 2005), which are often used with thiopurines. However, in the most likely scenario of combined use (inflammatory bowel disease), salicylates are usually initiated before azathioprine or 6-MP and are generally continued concurrently.…”

Interruption of Mesalamine and Reduction of the Blood Concentration of the Active Metabolites of Azathioprine: Possible Causes of Ulcerative Colitis Relapse

“…In support of this, mesalamine and sulfasalazine have been shown to inhibit TPMT in vitro. However, this inhibition occurs at a concentration of salicylates that should not be reached in the patients' tissues during the administration of the drug at therapeutic doses and, consequently, other unknown mechanisms could be involved [14]. The increase in the concentrations of TGN above the therapeutic range, consequent to the combination of thiopurines with salicylates, can increase the probability of adverse events, such as leucopenia [11].…”