作　　者： (邱海波）; (庄玮）; (王雪丁）; (黄民）; (周志伟）;

机构地区： 中山大学肿瘤防治中心胃外科华南肿瘤学国家重点实验室肿瘤医学协同创新中心,广州510060

出　　处： 《中华胃肠外科杂志》 2017年第9期1031-1034,共4页

摘　　要： 目的探讨胃肠间质瘤（GIST）代谢酶基因多态性对伊马替尼（IM）及其代谢物去甲基伊马替尼（NDI）药动学个体差异的影响。方法回顾性分析2014—2016年在中山大学附属肿瘤医院接受400 mg/d IM辅助治疗的118例GIST患者的临床资料。采用LC-MS/MS方法检测IM和NDI血药浓度。采用MassArray方法对CYP3A4 rs2242480、CYP1A2 rs762551、CYP2C19 rs28399505和NR1I2 rs3814057进行基因分型。血药浓度与基因多态性关联分析采用Whitney U检验，P ≤ 0.05表示显著相关，0.05 〈 P 〈 0.10提示潜在相关。结果118例GIST患者中男63例，女55例，中位年龄55（44~63）岁；肿瘤原发灶位于胃87例，肠道13例，其他部位18例。所有病例均接受了标准的400 mg/d IM治疗，IM谷浓度（CIM）为（1 501.1 ± 646.8）μg/L，NDI谷浓度（CNDI）为（221.7 ± 92.5）μg/L。关联分析结果显示，CYP2C19 rs28399505与IM和NDI血药浓度显著相关，TC型杂合子携带者的CIM和CNDI均明显低于TT型纯合子[CIM：（695.4 ± 202.9）μg/L比（1518.9 ± 716.8）μg/L，P= 0.002；CNDI：（133.3 ± 59.8）μg/L比（244.5 ± 99.1）μg/L，P= 0.028]；NR1I2 rs3814057与IM和NDI血药浓度均显示出潜在相关性（CIM：P= 0.079；CNDI：P= 0.082）；而CYP3A4 rs2242480和CYP1A2 rs762551则与IM和NDI血药浓度无相关性（均P 〉 0.10）。结论CYP2C19在IM代谢过程中可能具有重要作用，其基因多态性检测或有助于临床上IM药物监测的开展和个体化治疗决策。 ObjectiveTo investigate the influence of metabolic enzymes polymorphisms on variations of imatinib （IM） pharmacokinetics in gastrointestinal stromal tumors （GIST） patients.MethodsClinical data of 118 Chinese GIST patients receiving 400 mg/d IM at Sun Yat-sen University Cancer Center between 2014 and 2016 were retrospectively analyzed. The plasma concentration of imatinib mesylate （IM） and its main metabolic N-demethyl imatinib （NDI） were determined by LC-MS/MS. CYP3A4 rs2242480, CYP1A2 rs762551, CYP2C19 rs28399505 and NR1I2 rs3814057 were genotyped by MassArray system. Association between drug concentration and polymorphism was examined by Whitney U test. P ≤ 0.05 indicated close association and 0.05 〈 P 〈 0.10 indicated marginal association.ResultsAmong 118 GIST patients, 63 were male and 55 were female with a median age of 55 （44 to 63） years. Primary lesion location was the stomach in 87 cases, intestine in 13 cases and other sites in 18 cases. All the patients received standard 400 mg/d IM. Concentration of IM （CIM） was （1 501.1 ± 646.8） μg/L and concentration of NDI （CNDI） was （221.7 ± 92.5） μg/L. Association analysis showed that CYP2C19 rs28399505 was closely associated with concentration of IM and NDI （P= 0.002 and 0.028） . The concentration of IM and NDI in patients with TC heterozygote was significantly lower than those with wildtype TT[CIM： （695.4 ± 202.9） μg/L vs. （1 518.9 ± 716.8） μg/L, P= 0.002; CNDI： （133.3 ± 59.8） μg/L vs. （244.5 ± 99.1） μg/L, P= 0.028]. NR1I2 rs3814057 was marginally associated with concentration of IM and NDI （CIM： P= 0.079; CNDI： P= 0.082） , while CYP3A4 rs2242480 and CYP1A2 rs762551 were not associated with concentration of IM or NDI （all P 〉 0.10） .ConclusionsCYP2C19 may play an important role in IM metabolism. Detection of CYP2C19 polymorphism may be beneficial to clinical monitoring of IM and decision making of individualized treatment.

关 键 词： 胃肠间质瘤 伊马替尼 血药浓度 基因 基因