婴幼儿肝移植供受者的CYP3A5基因多态性对他克莫司药动学的影响  

Impact of CYP3A5 genotype of recipients and donors on Tacrolimus pharmacokinetics in Chinese pediatric liver transplant patients

作　　者：陈奕宽 薛峰[1] 沈丛欢[1] 韩龙志[1] 周韬[1] 杨太华[1] 卢军[1] 张建军[1] 夏强[1] 

机构地区：[1]上海交通大学医学院附属仁济医院肝脏外科肝移植,200127

出　　处：《中华器官移植杂志》2015年第1期1-6,共6页Chinese Journal of Organ Transplantation

基　　金：国家自然科学基金（81470847）;国家卫生部课题基金（IHECC08-201213）;上海市自然科学基金（12ZR1418300）;上海市卫生局新百人计划（XBR2011029）;上海市卫生局重点联合攻关项目（2013ZYJB0001）

摘　　要：目的研究婴幼儿肝移植供、受者的CYP3A5基因型对他克莫司（Tac）药动学的影响，从而建立适合婴幼儿肝移植受者的适合给药方案。方法将85对肝移植供者和婴幼儿受者根据CYP3A5基因型分为4组：受者表达／供者表达组（EX-R／EX-D组）27例，受者表达／供者不表达组（EX-R／NEX-D组）10例，受者不表达／供者表达组（NEX-R／EX-D组）15例，受者不表达／供者不表达组（NEX-R／NEx-D组）33例。比较并分析各组的Tae服用剂量和血药浓度／剂量值的相关性。结果NEX-R／NEX-D组受者Tac初始剂量为（0．19±0．08）mg·kg^-1·d^-1，与之相比较，EX-R／EX-D组受者的Tac初始剂量更高，为（0．26±0．09）mg·kg^-1·d^-1（P〈0．01），此后直到术后12个月后者Tac剂量始终较高。且EX-R／EX-D组受者的血Tac浓度达峰时间更长、药物代谢更快。CYP3A5基因型对于Tac代谢（即血药浓度／剂量）具有显著影响作用，占到36．85％，其中供者的CYP3A5基因型占主要作用，达到30．56％（P〈0．01）。结论肝移植术后受者Tac服用剂量的个体化差异与供、受者的CYP3A5基因多态性密切相关，术前检测供、受者的CYP3A5基因型可以预测肝移植术后Tac药动学，为Tac个体化用药提供可靠的参考指标。对于EX-R／EX-D受者Tac初始剂量可以为0．25～0.30mg·kg^-1·d^-1。Objective Little information is available regarding the impact of cytochrome P450 （CYP） 3A5 on the metabolism of tacrolimus （TAC） in infant liver transplantation. Therefore, the CYP3A5 genotype of Chinese pediatric recipients （intestine） as well as donors （graft liver） was analysed for the purpose of establishing an optimal dosage regimen in children. Method Eighty-five patients treated with TAC were divided into the following groups according to CYP3A5 genotype Eexpression of ＊ 1 allele. expression （EX） and non-expression （NEX）] for each recipient （R） and donor （D）： EX-R/EX-D （n = 27）, EX-R/NEX-D （n = 10）, NEX-R/EX-D （n = 15 ） and NEX-R/NEX-D （n = 33）. TAC daily dose requirement and concentration/dose ratios were analyzed. Result Initial TAC daily dose requirement was higher among EX-R/EX-D children than in those who didnt express CYP3A5 （0. 26 ± 0. 09 vs. 0. 19 ±0. 08 rag. kg^-1. d^-1, P〈 0. 01 ）. CYP3A5 expression contributed an overall of 36. 85 % to its concentration/dose ratios, and graft liver was a key determinant （30. 56%, P〈0. 01）. Conclusion CYP3A5 genotype in both recipients and donors significantly affects TAC pharmacokineties after liver transplantation in pediatric patients. Pre-operative assessment of CYP3A5 genotypes in both recipients and donors may be important to predict TAC pharmacokinetics, and administration of this drug using the appropriate dose and schedule can achieve the maximum benefit to patients. We suggest that pediatric patients carrying EX-R/EX-D genotype

关 键 词：细胞色素P450 CYP3A5 他克莫司 药代动力学 婴儿 肝移植 

分 类 号：R726.5[医药卫生—儿科]