Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease
Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease
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DOI：
10.1016/s0016-5085(00)70140-5
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发表时间：
2000-04-01
期刊：
影响因子：
29.4
通讯作者：
Seidman, EG
中科院分区：
文献类型：
--
作者：
Dubinsky, MC;Lamothe, S;Seidman, EG
背景和目标：6-巯基嘌呤（6-MP）的作用是通过其细胞内转化为6-硫代鸟嘌呤（6-TG）和6-甲基巯基嘌呤（6-MMP）核苷酸代谢物介导的，后者由巯基嘌呤甲基转移酶（TPMT）遗传控制。我们试图确定最佳治疗6-MP代谢物水平及其与药物诱导的毒性和TPMT基因型的相关性。在92名患有炎症性肠病的儿科患者中确定了治疗反应，同时与血液学、胰腺和肝脏实验室参数进行了比较，并与红细胞代谢物水平和TPMT基因型进行了比较。临床反应与6-TG水平高度相关（P <0.0001），但与任何其他变量无关，包括6-MMP水平、药物剂量、性别和合并用药。当6-TG水平> 235 pmol/8 × 10（8）红细胞时，治疗反应频率增加（P <0.001）。肝毒性与升高的6-MMP水平相关（> 5700 pmol/8 × 10（8）红细胞; P <0.05）。虽然白细胞减少与较高的6-TG水平相关（P <0.03），但仅在8%的应答者中观察到。TPMT杂合子患者（8/92）有较高的6-TG水平（P <0.0001），并且对治疗均有反应。结论：6-MP代谢物水平和TPMT基因分型可以帮助临床医生优化对6-MP的治疗反应，并识别药物诱导毒性风险增加的个体。
Background & Aims: The effects of 6-mercaptopurine (6-MP) are mediated via its intracellular conversion to 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) nucleotide metabolites, the latter genetically controlled by thiopurine methyltransferase (TPMT), We sought to determine optimal therapeutic 6-MP metabolite levels and their correlation with medication-induced toxicity and TPMT genotype, Methods: Therapeutic response was determined in 92 pediatric patients with inflammatory bowel disease coincidentally with hematologic, pancreatic, and hepatic laboratory parameters, and compared with erythrocyte metabolite levels and TPMT genotype, Results: Clinical response was highly correlated with 6-TG levels (P < 0.0001) but not with any other variable, including 6-MMP levels, drug dose, gender, and concurrent medications. The frequency of therapeutic response increased at 6-TG levels > 235 pmol/8 x 10(8) erythrocytes (P < 0.001). Hepatotoxicity correlated with elevated 6-MMP levels (>5700 pmol/8 x 10(8) erythrocytes; P < 0.05). Although leukopenia was associated with higher 6-TG levels (P < 0.03), it was observed in only 8% of responders. Patients heterozygous for TPMT (8/92) had higher 6-TG levels (P < 0.0001), and all responded to therapy. Conclusions: 6-MP metabolite levels and TPMT genotyping may assist clinicians in optimizing therapeutic response to 6-MP and identifying individuals at increased risk for drug-induced toxicity.