Thiopurine Maintenance Therapy for Ulcerative Colitis: The Clinical Significance of Monitoring 6-Thioguanine Nucleotide
Thiopurine Maintenance Therapy for Ulcerative Colitis: The Clinical Significance of Monitoring 6-Thioguanine Nucleotide
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DOI：
10.1002/ibd.21190
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发表时间：
2010-08-01
影响因子：
4.9
通讯作者：
Kubota, Takahiro
中科院分区：
文献类型：
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作者：
Hanai, Hiroyuki;Iida, Takayuki;Kubota, Takahiro
背景：6-巯基嘌呤(6-MP)是治疗溃疡性结肠炎(UC)的有效维持性药物，但骨髓抑制等毒副作用限制了其临床疗效。在血液中，6-硫代鸟苷(6-TGN)是由6-MP形成的，它介导了6-MP的治疗效果和大部分毒性。6吨的水平取决于硫代嘌呤甲基转移酶(TPMT)的活性，TPMT作为其3种多态形式中的一种遗传，具有低、中或正常/高活性。因此，6-MP的剂量需要药物遗传学的指导。方法：静止期UC患者接受6-MP作为维持治疗，用高效液相色谱法测定红细胞中6-TGN的浓度。在一项初步研究中，50例患者在12周内每天口服30 mg 6-Mp，以确定6-TGN血药浓度的时程。257例患者根据RBC 6-TGN、白细胞计数和体重分阶段给予6-MP 15 80 mg/d，监测6-MP的疗效和安全性。结果：6-MP 30 mg/d时，RBC 6-TON在4~8周内达到高峰。在主要剂量研究中，在1年观察期间保持缓解的患者的平均红细胞6吨水平为322.3+/-119.5 pmole/8×10(8)红细胞，而复发患者(n=19)的平均红细胞6吨水平为204.8+/-78.7pmole/8×10(8)红细胞(P<；0.001)。骨髓抑制几乎仅见于高6-TGN浓度范围。结论：通过定期检测接受6-MP维持治疗的静止期UC患者的RBC-6-TGN，可以监测骨髓抑制及其他毒副作用。潜在地，这一策略应该使医生能够避免与硫嘌呤相关的不良反应，并确定可能从6-MP维持疗法中受益最大的个体。
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-TON 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-TON peaked over 4-8 weeks. In the main dosing study, the mean RBC 6-TON 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-TON 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.