肝移植术后早期肝功能指标与供受体CYP3A5基因多态性对他克莫司血药浓度的影响  

The Effect of Liver Function Indicators and Donor-recipient CYP3A5 Genetic Polymorphism on the Blood Concentration of Tacrolimus in the Early Postoperative Period After Liver Transplantation

作　　者：李洁玲 陈攀[1] 陈孝[1] 郭志勇[2] 刘晓曼[1] LI Jieling;CHEN Pan;CHEN Xiao;GUO Zhiyong;LIU Xiaoman(Department of Pharmacy,The First Affliated Hospital,Sun Yat-sen University,Guangzhou,Guangdong 510080,China;Organ Transplant Center,The First Affliated Hospital,Sun Yat-sen University,Guangzhou,Guangdong 510080,China;School of Pharmaceutical sciences,Sun Yat-sen University,Guangzhou,Guangdong 510006,China)

机构地区：[1]中山大学附属第一医院药学部,广东广州510080 [2]中山大学附属第一医院器官移植科,广东广州510080 [3]中山大学药学院,广东广州510006

出　　处：《今日药学》2024年第8期601-606,共6页Pharmacy Today

基　　金：国家自然科学基金项目(82104291);中华国际医学交流基金会-中华医学会临床药学分会科研基金(Z-2021-46-2101-2023);广东省医院药学研究基金(2024A37,2023KP21)。

摘　　要：目的 探讨肝移植术后1个月内受体的肝功能指标和他克莫司血药浓度的变化,以及供体和受体的CYP3A5基因型对他克莫司血药浓度的综合影响。方法 回顾性收集2016~2020年在中山大学附属第一医院行肝移植术的患者178例,记录术后1个月内的血清丙氨酸氨基转移酶(ALT)、谷氨酸氨基转移酶(AST)、总胆红素(TBIL)和直接胆红素(DBIL)水平,以及他克莫司剂量校正谷浓度(C/D值)。采用DNA芯片检测肝移植供受体的CYP3A5基因型,CYP3A5*1/*1和CYP3A5*1/*3为表达者,CYP3A5*3/*3为非表达者。综合供体和受体的CYP3A5基因型将患者分为4组,即受体表达/供体表达组(Re De)、受体表达/供体非表达组(Re Dn)、受体非表达/供体表达组(Rn De)、受体非表达/供体非表达组(Rn Dn),分析不同基因型组合对术后早期他克莫司C/D值的影响。结果 患者肝移植术后第1~2周(恢复期)的肝功能指标(ALT、AST、TBIL和DBIL)水平显著高于第3~4周(稳定期)(P<0.05)。综合供受体CYP3A5基因型分析结果显示,组内分析中,每组患者在术后第1~4周不同时间点的组内他克莫司C/D值均无显著差异。组间分析中,在术后第1~4周,Rn Dn组的他克莫司C/D值每周均显著高于Re De组(P<0.05);术后第1~3周,Re Dn组患者的他克莫司C/D值每周均显著高于Re De组(P<0.05),Rn Dn患者的他克莫司C/D值每周均显著高于Rn De组(P<0.05)。结论 肝移植术后早期他克莫司的血药浓度在肝功能恢复期与稳定期之间无明显差异,术后早期受体和供体CYP3A5基因型均会影响他克莫司血药浓度,可用于指导他克莫司的个体化用药方案。OBJECTIVE This study aims to explore the variations in liver function indicators and tacrolimus blood concentration among recipients,as well as the combined effect of donors'and recipients'CYP3A5 polymorphism on tacrolimus blood concentration in the first month after liver transplantation.METHODS SClinical data and blood samples were collected from 178 patients who underwent liver transplantation at the First Affiliated Hospital of Sun Yat-sen University between 2016 and 2020.Serum levels of alanine aminotransferase(ALT),glutamate aminotransferase(AST),total bilirubin(TBIL),and direct bilirubin(DBIL),as well as the dose-adjusted trough concentration(C/D ratio)of tacrolimus,in the first month after transplantation were recorded.The CYP3A5 genotype of liver transplant donors and recipients was detected by DNA chip.Patients with CYP3A5*1/*1 and CYP3A5*1/*3 were classified as expressers,while those with CYP3A5*3/*3 were classified as non-expressers.Patients were categorized into four groups to analyze the combined ffect of donors'and recipients'CYP3A5 polymorphism on tacrolimus C/D ratio:recipient expresser/donor expresser group(ReDe),recipient expresser/donor non-expresser group(ReDn),recipient non-expresser/donor expresser group(RnDe),and recipient non-expresser/donor non-expresser group(RnDn).RESULTS The levels of liver function indicators(ALT,AST,TBIL,and DBIL)in the first and second weeks after liver transplantation(convalescence phase)were significantly higher than those in the third and fourth weeks(stationary phase,P<0.05).The analysis of the donor-recipient CYP3A5 genotype revealed that within each group,there were no significant differences in the tacrolimus C/D ratios at different time points during weeks 1 to 4 postoperatively.However,in inter-group analysis,the tacrolimus C/D ratios of the RnDn group were significantly higher than the ReDe group each week(P<0.05).During weeks I to 3 postoperatively,the tacrolimus C/D ratios of the ReDn group were significantly higher than in the ReDe group each week(P<0.

关 键 词：肝移植 肝功能指标 他克莫司 CYP3A5 基因多态性 血药浓度 

分 类 号：R969[医药卫生—药理学]