Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease
Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease
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DOI：
10.1111/j.1365-2036.2008.03788.x
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发表时间：
2008-10-15
影响因子：
7.6
通讯作者：
Sanderson, J.
中科院分区：
文献类型：
--
作者：
Ansari, A.;Arenas, M.;Sanderson, J.
背景：三分之一接受硫唑嘌呤（AZA）治疗的炎症性肠病（IBD）患者因副作用或缺乏临床反应而退出治疗。目的探讨药物遗传位点或代谢物浓度是否能解释AZA的临床反应或副作用。方法IBD患者给予2 mg/kg的AZA治疗，不进行剂量递增或调整。随访6个月，检测临床反应、硫嘌呤甲基转移酶（TPMT）活性和硫鸟嘌呤核苷酸（TGN）浓度。所有患者均进行肌苷三磷酸酶（ITPase）和TPMT基因分型。将临床反应和副作用与这些变量进行比较。结果对227例患者进行了分析。39%的人因不良反应而退出。杂合子TPMT基因型强烈预测不良反应（79%杂合子vs 35%野生型TPMT， P < 0.001）。ITPA 94C > A突变与流感样症状引起的停药相关（P = 0.014）。与TPMT高于35 pmol/h/mg/Hb相比，基线TPMT活性低于35 pmol/h/mg/Hb与更大的临床反应机会相关（分别为81%对43%，P < 0.001）。平均TGN水平高于100的患者更有可能产生应答（P = 0.0017）。结论stpmt检测可预测不良反应，降低临床反应机会（TPMT bbb35 pmol/h/mg/Hb）。ITPase缺乏是不良反应的预测因子，TGN浓度高于100与临床反应相关。
BackgroundOne-third of patients with inflammatory bowel disease (IBD) receiving azathioprine (AZA) withdraw treatment due to side effects or lack of clinical response.AimTo investigate whether pharmacogenetic loci or metabolite concentrations explain clinical response or side effects to AZA.MethodsPatients with IBD were given 2 mg/kg of AZA without dose escalation or adjustment. Serial clinical response, thiopurine methyl transferase (TPMT) activity and thioguanine nucleotide (TGN) concentrations were measured over 6 months. All patients were genotyped for inosine triphosphatase (ITPase) and TPMT. Clinical response and side effects were compared to these variables.ResultsTwo hundred and seven patients were analysed. Thirty-nine per cent withdrew due to adverse effects. Heterozygous TPMT genotype strongly predicted adverse effects (79% heterozygous vs. 35% wild-type TPMT, P < 0.001). The ITPA 94C > A mutation was associated with withdrawal due to flu-like symptoms (P = 0.014). A baseline TPMT activity below 35 pmol/h/mg/Hb was associated with a greater chance of clinical response compared with a TPMT above 35 pmol/h/mg/Hb (81% vs. 43% respectively, P < 0.001). Patients achieving a mean TGN level above 100 were significantly more likely to respond (P = 0.0017).ConclusionsTPMT testing predicts adverse effects and reduced chance of clinical response (TPMT > 35 pmol/h/mg/Hb). ITPase deficiency is a predictor of adverse effects and TGN concentrations above 100 correlate with clinical response.