Thiopurine maintenance therapy for ulcerative colitis: the clinical significance of monitoring 6-thioguanine nucleotide
| Autor: | Hiroyuki Hanai, Yoshisuke Hosoda, Takayuki Iida, Satou Yoshirou, Akihiko Oohata, Masanobu Kageoka, Ichita Miwa, Jinrou Abe, Yasuhiko Maruyama, Ken Takeuchi, Osamu Arai, Kentarou Ikeya, Takahiro Kubota, Fumitoshi Watanabe |
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| Rok vydání: | 2010 |
| Předmět: |
Adult
Erythrocytes Adolescent Prednisolone Pharmacology Young Adult Maintenance therapy Bone Marrow White blood cell medicine Immunology and Allergy Humans Clinical significance Dosing Leukapheresis Adverse effect Mesalamine Thioguanine Bone Marrow Diseases Aged Thiopurine methyltransferase biology business.industry Mercaptopurine Gastroenterology Methyltransferases Middle Aged medicine.disease Ulcerative colitis medicine.anatomical_structure Treatment Outcome Bone marrow suppression biology.protein Colitis Ulcerative Drug Monitoring business Immunosuppressive Agents |
| Zdroj: | Inflammatory bowel diseases. 16(8) |
| ISSN: | 1536-4844 |
| Popis: | 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) |
| Databáze: | OpenAIRE |
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