Thiopurine maintenance therapy for ulcerative colitis: the clinical significance of monitoring 6-thioguanine nucleotide.

Abstract

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 x 10(8) RBC versus 204.8 +/- 78.7 pmole/8 x 10(8) 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.

• Authors: 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
• Journal: Inflammatory bowel diseases (Inflamm Bowel Dis) Vol. 16 Issue 8 Pg. 1376-81 (Aug 2010) ISSN: 1536-4844 [Electronic] England
• PMID: 20049951 (Publication Type: Journal Article, Randomized Controlled Trial)

Chemical References

• Immunosuppressive Agents
• Mesalamine
• Prednisolone
• Mercaptopurine
• Methyltransferases
• thiopurine methyltransferase
• Thioguanine

Topics

• Adolescent
• Adult
• Aged
• Bone Marrow (drug effects)
• Bone Marrow Diseases (chemically induced)
• Colitis, Ulcerative (drug therapy)
• Drug Monitoring
• Erythrocytes (chemistry, drug effects)
• Humans
• Immunosuppressive Agents (administration & dosage, adverse effects, pharmacokinetics)
• Leukapheresis
• Mercaptopurine (administration & dosage, adverse effects, pharmacokinetics)
• Mesalamine (therapeutic use)
• Methyltransferases (analysis, genetics)
• Middle Aged
• Prednisolone (therapeutic use)
• Thioguanine (blood)
• Treatment Outcome
• Young Adult