供受体CYP3A5基因型对肝移植术后早期他克莫司谷浓度的影响作用及其临床意义  

Influence of donor and recipient CYP3A5 genotype on tacrolimus trough concentrations in the early stage after liver transplantation and its clinical significance

作　　者：吴懿[1] 方芳[2] 陈瑛[1] 樊军卫[1] WU Yi;FANG Fang;CHEN Ying;Fan Junwei(Department of Hepatobiliary Pancreatic Surgery,Shanghai General Hospital,Shanghai 200080,China;Nursing Department,Shanghai General Hospital,Shanghai 200080,China)

机构地区：[1]上海市第一人民医院肝胆胰外科,上海200080 [2]上海市第一人民医院护理部,上海200080

出　　处：《中国临床药理学与治疗学》2021年第6期631-639,共9页Chinese Journal of Clinical Pharmacology and Therapeutics

基　　金：国家自然科学基金委联合基金项目重点支持项目(U1604282);上海申康医院发展中心临床科技创新项目(SHDC12018X15);上海市“医苑新星”青年医学人才培养资助计划(吴懿);上海交通大学“医工(理)交叉研究基金”项目(YG2017MS2);上海市第一人民医院临床研究创新团队项目(CTCCR-2018BP01)。

摘　　要：目的:回顾性分析治疗药物浓度监测(TDM)策略下,供受体CYP3A5 rs776746基因分型对肝移植术后早期他克莫司谷浓度的影响作用及其临床意义。方法:根据入选标准收集2015年1月到2019年3月上海市第一人民医院肝移植患者125例,临床资料包括术后28天的临床药理学参数、肝功能以及随访新发糖尿病(new onset diabetes mellitus,NODM)情况。应用定量PCR技术对供体和受体细胞色素P450家族成员3A5(CYP3A5)基因rs776746位点进行分型。结果:术后第一周他克莫司谷浓度中位数(median trough concentration,Ct_(med))、谷浓度最大值(maximum trough concentration,Ct_(max))分别为(8.3±7.0)ng/mL、(11.2±12.9)ng/mL。供体和受体联合CYP3A5基因分型可将患者分为4个亚组:供体和受体均为AA/AG组、供体AA/AG+受体GG组、供体GG+受体AA/AG组、供体GG+受体GG组。各亚组患者术后第一周Ctmed、Ct_(max)均有统计学差异(P<0.01)。接收者操作特征(ROC)分析显示Ct_(max)可预测NODM,曲线下面积(AUC)为0.7168(P=0.0005),最佳诊断阈值浓度为14.4 ng/mL;而Ctmed对NODM没有预测价值(P=0.1936)。多因素Logistic回归分析显示,Ct_(max)异常过高(大于等于14.4 ng/mL,OR:17.796,P=0.014)和术前血糖水平(OR:5.076,P=0.043)、术前总胆固醇水平(OR:3.752,P=0.022)、术后激素治疗(OR:12.846,P=0.015)为NODM发生的独立危险因素。供受体CYP3A5基因型对Ct_(max)有显著影响,四个亚组肝移植术后早期Ct_(max)大于等于14.4 ng/mL患者分别为14.70%(5/34)、33.33%(12/36)、61.11%(11/18)、78.57(22/28),四组间比较均有统计学差异(P<0.0001)。结论:TDM结合供受体CYP3A5 rs776746基因分型指导肝移植患者个体化用药有助于减少Ct_(max)异常过高和NODM发生。AIM:To analyze the influence of donor and recipient CYP3A5 genotype on tacrolimus trough concentrations in the early stage after liver transplantation and its clinical significance under therapeutic drug monitoring(TDM)strategy retrospectively.METHODS:A total of 125 patients undergoing liver transplantation in Shanghai General Hospital from January 2015 to March 2019 were involved in this study.Clinical pharmacology parameters and liver function indexes from 1 to 28 days after operation,the occurrence of new onset diabetes mellitus(NODM)was collected.Donor and recipient cytochrome P450,family 3,subfamily A,polypeptide 5(CYP3A5)gene rs776746 locus were genotyped by RT-PCR technology.RESULTS:Median trough concentration(Ct_(med))and maximum trough concentration(Ct_(max))of tacrolimus in the first week after liver transplantation were(8.3±7.0)ng/mL,(11.2±12.9)ng/mL,respectively.Patients were divided 4 subgroups according to CYPA35 rs776746 genotype:recipients with AA/AG genotype carrying AA/AG genotype donor,recipients with AA/AG genotype carrying GG genotype donor,recipients with GG genotype carrying AA/AG genotype donor and recipients with GG genotype carrying GG genotype donor.There was significant difference of Ct med and Ct_(max)in each subgroup(P<0.01).ROC curve analysis showed that the AUC of tacrolimus Ct_(max)in predicting NODM was 0.7168(P=0.0005)and optimal diagnostic threshold concentration was 14.4 ng/mL.Ct med couldn't predict NODM(P=0.1936).Preoperative blood glucose level(OR:5.076,P=0.043),preoperative total cholesterol level(OR:3.752,P=0.022),glucocorticoid therapy after operation(OR:12.846,P=0.015)and tacrolimus Ct_(max)(OR:17.796,P=0.014)were independent risk factors of NODM.Donor and recipient CYP3A5 genotype had a marked impact on Ct_(max).The proportion of patients with Ct_(max)greater than or equal to 14.4 ng/mL in each subgroup were 14.70%(5/34),33.33%(12/36),61.11%(11/18)and 78.57(22/28),there were significant differences among the four groups(P<0.0001).CONCLUSION:To combine TDM strategy an

关 键 词：肝移植 他克莫司 谷浓度 新发糖尿病 细胞色素P450家族成员3A5 

分 类 号：R575[医药卫生—消化系统] R617[医药卫生—内科学]