克唑替尼治疗肺癌肝毒性与CYP3A5基因多态性的相关性分析  

Relationship between Crizotinib Hepatotoxicity and CYP3A5~*3 Genotype

作　　者：顾鹏[1] 王璇[1] 周月琴[2,3] Gu Peng;Wang Xuan;Zhou Yueqin(Department of Pharmacy,Xinqiao Hospital,Army Medical University（Third Military MedicalUniversity）Chongqing 400037,China;Quality Control Office,Chongqing Emergency Medical Center,Chongqing 400014,China;Quality Control Office,Affiliated Central Hospital of Chongqing University,Chongqing 400014,China)

机构地区：[1]陆军军医大学(第三军医大学)新桥医院药剂科,重庆400037 [2]重庆市急救医疗中心质控办,重庆400014 [3]重庆大学附属中心医院质控办,重庆400014

出　　处：《中华肺部疾病杂志（电子版）》2018年第5期573-577,共5页Chinese Journal of Lung Diseases(Electronic Edition)

基　　金：重庆市科委联合医学科研项目(QNXM20181733)

摘　　要：目的探讨克唑替尼治疗肺癌中肝毒性的发生与CYP3A5基因多态性的相关性。方法选择2013年1月至2017年12月5年在陆军军医大学(第三军医大学)新桥医院采用克唑替尼治疗非小细胞肺癌(non-small cell lung cancer,NSCLC)患者84例,以血清转氨酶或胆红素升高为肝毒性表现,分为肝毒性组32例,无肝毒性组52例。检测患者CYP3A5基因型,肝功能损伤情况,经非条件性二元Logistic回归分析患者肝毒性的发生与CYP3A5基因多态性的相关性。结果治疗后发生肝毒性的患者与未发生肝毒性的患者比较,两组的年龄、性别、身高及体质量差异均无统计学意义(P>0.05)。肝毒性组发生1级肝功能损伤的有16例,发生2级肝功能损伤的有8例,发生3级肝功能损伤的有8例,没有患者发生4级肝功能损伤。其中有4例肝功损伤3级患者发生了INR值的轻度升高。肝毒性发生的中位时间为41 d(15～162 d)。Logistic回归分析未发现CYP3A5基因型与克唑替尼治疗肺癌所致的肝毒性有显著性关联。发生2级和3级肝毒性的16例患者均再次服用小剂量克唑替尼(250 mg/d),其中6例为同时使用了CYP3A4抑制剂的患者:氨氯地平片(3例)、硝苯地平(2例)、地尔硫(1例)个。具有*3/*3的5例患者再次发生了克唑替尼导致的肝毒性,另外1例具有*1/*3的患者没有再发生肝毒性。结论 CYP3A5活性降低不能直接预示克唑替尼肝毒性的发生,但也存在一定相关性。当CYP3A4活性被抑制时,CYP3A5活性降低可能是克唑替尼致肝毒性的原因之一。Objective To investigate the possible relationship between the occurrence of hepatotoxicityin the treatment of lung cancer by crizotinib and CYP3A5 gene polymorphism. Methods Clinical data werecollected from 84 patients who had non-small cell lung cancer（NSCLC） and received crizotinib in the SecondAffiliated Hospital of the Third Military Medical University five years from 2013.1 to 2017.12. Increased serumtransaminase and bilirubin were the sign of hepatotoxicity, based on the above performance, the patients weredivided into two groups： 32 patients in hepatotoxic group and 52 patients in non-hepatotoxic group. Thesepatients were tested for CYP3A5 genotype and liver function injury, and statistically analyzed for therelationship between the occurrence of hepatotoxicity and the differences in CYP3A5 genotypes using non-conditional binary Logistic regression analysis. Results There were no significant differences in age, gender,height and body weight between the patients with hepatotoxicity after treatment and those without hepatotoxicity（P〉0.05）. In the hepatotoxic group, liver function injury one grade were 16 cases, two grade were 8 cases,three grade were 8 cases, four grade did not occur. 4 patients of the liver function injury three grade had the INR value increased slightly. The median time to onset of hepatotoxicity was 41 days （ 15 ～ 162 days）. Nosignificant association was found between CYP3A5 genotype and hepatic toxicity induced by crizotinib accordingto the non-conditional binary logistic regression analysis. 16 patients of the liver function injury two and threegrades received a small dose of crizotinib （ 250 mg once daily）, and 6 patients among them used CYP3A4inhibitors at the same time： amlodipine tablet （3 cases）, nifedipine （2 cases）, diltiazem （1 cases）. 5 cases of-3 /-3 hepatic toxicity caused by crizotinib occurred again, and another patient with -1 /-3 did not develophepatotoxicity. Conclusion The decreased activity of CYP3A5 does not directly predict the oc

关 键 词：支气管肺癌 克唑替尼 CYP3A5 基因多态性 肝毒性 

分 类 号：R734.2[医药卫生—肿瘤]