Thiopurine maintenance therapy for ulcerative colitis: The clinical significance of monitoring 6‐thioguanine nucleotide

Background: 6‐Mercaptopurine (6‐MP) is an effective maintenance medication in patients with ulcerative colitis (UC), but toxic effects like myelosuppression limit its clinical benefit. In the blood, 6‐thioguanine (6‐TGN) is formed from 6‐MP and mediates the therapeutic efficacy and most of the toxicities of 6‐MP. The level of 6‐TGN depends on the activity of thiopurine methyltransferase (TPMT), inherited as 1 of its 3 polymorphic forms with low, moderate, or normal/high activity. Accordingly, the 6‐MP dose needs to be pharmacogenetically guided. Methods: Patients with quiescent UC received 6‐MP as maintenance therapy and 6‐TGN was assayed as its concentrations in red blood cells (RBCs) done by high‐performance liquid chromatography. In a preliminary investigation, 30 mg/day 6‐MP (n = 50) was given orally over 12 weeks to determine the time course of blood 6‐TGN level. Then 257 patients were given 6‐MP at 15–80 mg/day in a stepwise manner based on RBC 6‐TGN, white blood cell count, and body weight to monitor 6‐MP efficacy and safety profiles. Results: At 30 mg/day 6‐MP, RBC 6‐TGN peaked over 4–8 weeks. In the main dosing study, the mean RBC 6‐TGN level in patients who remained in remission during the 1‐year observation time (n = 151) was 322.3 ± 119.5 pmole/8 × 108 RBC versus 204.8 ± 78.7 pmole/8 × 108 RBC in patients (n = 19) who relapsed (P < 0.001). Bone marrow suppression was seen almost exclusively at high 6‐TGN concentration ranges. Further, a regression plot showed an inverse relationship between 6‐TGN levels in RBC and TPMT enzyme activity. Conclusions: By regularly measuring RBC 6‐TGN in patients with quiescent UC receiving 6‐MP as maintenance therapy, we could monitor bone marrow suppression as well as other toxic side effects. Potentially, this strategy should enable physicians to avoid thiopurine‐related adverse effects and identify individuals who may benefit most from 6‐MP maintenance therapy. (Inflamm Bowel Dis 2010)