Thiopurine maintenance therapy for ulcerative colitis: The clinical significance of monitoring 6-thioguanine nucleotide
✍ Scribed by Hiroyuki Hanai; Takayuki Iida; Ken Takeuchi; Osamu Arai; Fumitoshi Watanabe; Jinrou Abe; Yasuhiko Maruyama; Akihiko Oohata; Kentarou Ikeya; Masanobu Kageoka; Ichita Miwa; Satou Yoshirou; Yoshisuke Hosoda; Takahiro Kubota
- Publisher
- John Wiley and Sons
- Year
- 2010
- Tongue
- English
- Weight
- 270 KB
- Volume
- 16
- Category
- Article
- ISSN
- 1078-0998
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✦ Synopsis
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 ¼ 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 ¼ 151) was 322.3 6 119.5 pmole/8 Â 10 8 RBC versus 204.8 6 78.7 pmole/8 Â 10 8 RBC in patients (n ¼ 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.