Qiu Haibo, Zhuang Wei, Wang Xueding, Huang Min, Zhou Zhiwei
Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
nstitute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
Zhonghua Wei Chang Wai Ke Za Zhi. 2017 Sep 25;20(9):1031-1034.
To investigate the influence of metabolic enzymes polymorphisms on variations of imatinib (IM) pharmacokinetics in gastrointestinal stromal tumors (GIST) patients.
Clinical 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.
Among 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 (C) was (1 501.1±646.8) μg/L and concentration of NDI (C) 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 [C: (695.4±202.9) μg/L vs. (1 518.9±716.8) μg/L, P=0.002; C:(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(C:P=0.079; C:P=0.082), while CYP3A4 rs2242480 and CYP1A2 rs762551 were not associated with concentration of IM or NDI(all P>0.10).
CYP2C19 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.
探讨代谢酶基因多态性对胃肠道间质瘤（GIST）患者伊马替尼（IM）药代动力学变化的影响。
回顾性分析2014年至2016年在中山大学肿瘤防治中心接受每日400 mg IM治疗的118例中国GIST患者的临床资料。采用液相色谱 - 串联质谱法测定甲磺酸伊马替尼（IM）及其主要代谢产物N - 去甲基伊马替尼（NDI）的血浆浓度。采用MassArray系统对CYP3A4 rs2242480、CYP1A2 rs762551、CYP2C19 rs28399505和NR1I2 rs3814057进行基因分型。通过惠特尼U检验检测药物浓度与基因多态性之间的关联。P≤0.05表示密切关联，0.05 < P < 0.10表示边缘关联。
118例GIST患者中，男性63例，女性55例，中位年龄55（44至63）岁。原发灶位于胃87例，肠道13例，其他部位18例。所有患者均接受标准的每日400 mg IM治疗。IM浓度（C）为（1501.1±646.8）μg/L，NDI浓度（C）为（221.7±92.5）μg/L。关联分析显示，CYP2C19 rs28399505与IM和NDI浓度密切相关（P = 0.002和0.028）。TC杂合子患者的IM和NDI浓度显著低于野生型TT患者[C：（695.4±202.9）μg/L对（1518.9±716.8）μg/L，P = 0.002；C：（133.3±59.8）μg/L对（244.5±99.1）μg/L，P = 0.028]。NR1I2 rs3814057与IM和NDI浓度存在边缘关联（C：P = 0.079；C：P = 0.082），而CYP3A4 rs2242480和CYP1A2 rs762551与IM或NDI浓度无关（所有P>0.10）。
CYP2C19可能在IM代谢中起重要作用。检测CYP2C19基因多态性可能有助于IM的临床监测和个体化治疗决策。
