Drake University College of Pharmacy and Health Sciences, Des Moines, Iowa.
Iowa Methodist Medical Center-University of Iowa Medical Residency Program, Des Moines, Iowa.
Pharmacotherapy. 2018 Feb;38(2):259-270. doi: 10.1002/phar.2067. Epub 2018 Jan 10.
Thiopurine drugs, including azathioprine and 6-mercaptopurine, are used commonly in patients with inflammatory bowel disease for maintenance of remission. Although generally well tolerated, adverse effects lead to discontinuation in a significant minority of patients. Pharmacogenomic studies have suggested that metabolic breakdown of azathioprine in an individual is genetically determined. Coupled with the fact that certain thiopurine metabolites, notably 6-thioguanine nucleotide and 6-methylmercaptopurine, are associated with antiinflammatory effects and adverse effects, respectively, some investigators have examined intentionally shunting the metabolism of azathioprine toward increasing 6-thioguanine nucleotide levels by using low doses of the xanthine oxidoreductase inhibitor allopurinol to improve efficacy and decrease toxicity of azathioprine in patients with inflammatory bowel disease. We performed a search of the MEDLINE and Embase databases for basic and clinical research reports of this modality. Pertinent articles were retrieved, reviewed, and assessed by the authors. Case series, cohort studies, and one randomized trial have investigated adding allopurinol to azathioprine therapy in patients with inflammatory bowel disease. Most reports primarily examined metabolite levels in these patients. In general, the literature suggests that this modality was successful at significantly increasing 6-thioguanine nucleotide levels while decreasing 6-methylmercaptopurine levels. Several small reports have suggested that patients with increased 6-thioguanine nucleotide levels had improved symptoms or symptom remission. Adverse effects and discontinuation rates remained similar or were improved in patients who were taking a thiopurine and started allopurinol. In conclusion, the addition of allopurinol may be an option for optimizing thiopurine metabolite production in select patients with low 6-thioguanine nucleotide levels. Appropriate care and monitoring of these patients are mandatory to prevent neutropenia or other adverse effects.
硫唑嘌呤类药物，包括硫唑嘌呤和 6-巯基嘌呤，常用于炎症性肠病患者的缓解期维持治疗。虽然通常耐受性良好，但不良反应导致少数患者停药。药物基因组学研究表明，个体中硫唑嘌呤的代谢分解在遗传上是确定的。再加上某些硫嘌呤代谢物，特别是 6-硫鸟嘌呤核苷酸和 6-甲基巯基嘌呤，分别与抗炎作用和不良反应有关，一些研究人员通过使用低剂量黄嘌呤氧化还原酶抑制剂别嘌醇有意引导硫唑嘌呤的代谢，以增加 6-硫鸟嘌呤核苷酸水平，从而提高炎症性肠病患者硫唑嘌呤的疗效并降低其毒性。我们在 MEDLINE 和 Embase 数据库中搜索了这种方法的基础和临床研究报告。检索、回顾和评估了作者的相关文章。病例系列、队列研究和一项随机试验研究了在炎症性肠病患者中添加别嘌醇治疗硫唑嘌呤的方法。大多数报告主要检查了这些患者的代谢物水平。总的来说，文献表明，这种方法在显著增加 6-硫鸟嘌呤核苷酸水平的同时降低 6-甲基巯基嘌呤水平方面是成功的。一些小型报告表明，6-硫鸟嘌呤核苷酸水平升高的患者症状或症状缓解得到改善。接受硫嘌呤并开始使用别嘌醇的患者的不良反应和停药率保持相似或改善。总之，在选择 6-硫鸟嘌呤核苷酸水平较低的患者中，添加别嘌醇可能是优化硫嘌呤代谢产物生成的一种选择。必须对这些患者进行适当的护理和监测，以防止中性粒细胞减少症或其他不良反应。
