Influence of 5‐aminosalicylic acid on 6‐thioguanosine phosphate metabolite levels: a prospective study in patients under steady thiopurine therapy

Background and purpose:  5‐aminosalicylate (5‐ASA) raises levels of 6‐thioguanine nucleotides (6‐TGN), the active metabolites of thiopurines such as azathioprine (AZA). Changes in levels of each individual TGN – 6‐thioguanosine mono‐, di‐ and triphosphate (6‐TGMP, 6‐TGDP, 6‐TGTP) – and of 6‐methylmercaptopurine ribonucleotides (6‐MMPR) after 5‐ASA are not known.Experimental approach:  Effects of increasing 5‐ASA doses on AZA metabolites were investigated prospectively in 22 patients with inflammatory bowel disease in 4‐week study periods. Patients started with 2 g 5‐ASA daily, and then were increased to 4 g daily and followed by a washout period. Thiopurine doses remained unchanged throughout the entire study. Levels of 6‐TGMP, 6‐TGDP, 6‐TGTP and 6‐MMPR as well as of 5‐ASA and N‐acetyl‐5‐aminosalicylic acid (N‐Ac‐5‐ASA) were determined each study period.Key results:  Median baseline levels in 17 patients of 6‐TGDP, 6‐TGTP and 6‐MMPR were 52, 319 and 1676 pmol per 8 × 108 red blood cells respectively. After co‐administration of 2 g 5‐ASA daily, median 6‐TGDP and 6‐TGTP levels increased but median 6‐MMPR levels were unchanged. Increasing 5‐ASA to 4 g daily did not affect median 6‐TGDP and 6‐TGTP levels, but median 6‐MMPR levels decreased. After discontinuation of 5‐ASA, both 6‐TGDP and 6‐TGTP levels decreased and median 6‐MMPR levels increased. The 6‐TGTP/(6‐TGDP+6‐TGTP)‐ratio did not change during the study, but 6‐MMPR/6‐TGN ratios decreased.Conclusions and implications:  Individual 6‐TGN metabolites increased after addition of 5‐ASA, but 6‐MMPR‐levels and the 6‐MMPR/6‐TGN ratios decreased. Further studies are needed to decide whether this pharmacokinetic interaction would result in improvement of efficacy and/or increased risk of toxicity of AZA.