Combinational effect of intestinal and hepatic CYP3A5 genotypes on tacrolimus pharmacokinetics in recipients of living donor liver transplantation.
Combinational effect of intestinal and hepatic CYP3A5 genotypes on tacrolimus pharmacokinetics in recipients of living donor liver transplantation.
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DOI：
10.1097/tp.0b013e318263700a
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发表时间：
2012-10-27
期刊：
影响因子：
6.2
通讯作者：
Oh JM
中科院分区：
文献类型：
--
作者：
Ji E;Choi L;Suh KS;Cho JY;Han N;Oh JM
对于活体肝移植，考虑到肝再生时间，受体自体肠和供体肝移植物的CYP 3A 5基因型与他克莫司药代动力学的遗传关联尚未得到完全解释。本研究的目的是研究受试者-供者联合CYP 3A 5基因型对血液中他克莫司剂量标准化浓度（C/D比值）的纵向影响。在4年的随访中，对58名韩国成人活体肝移植受者使用他克莫司为基础的免疫抑制剂进行了他克莫司血药浓度测定。对受体和供体的CYP 3A 5进行基因分型，并在调整包括人口统计学和临床变量在内的协变量后，评价了作为时间函数的供体-供体组合遗传效应对他克莫司C/D比值的影响。在整个研究期间，从CYP 3A 5表达者供体移植的CYP 3A 5表达者受体始终具有最小的C/D比，而从CYP 3A 5非表达者供体移植的CYP 3A 5表达者受体具有中间值，从CYP 3A 5非表达者供体移植的CYP 3A 5非表达者受体具有最大的C/D比（所有p < 0.01）。从CYP 3A 5表达供体移植的CYP 3A 5非表达受体在第一个月表现出C/D比从最大到中等的显著下降。受者和供者的CYP 3A 5基因型是影响他克莫司药动学变异性的重要因素。移植后随时间的推移，受体-供体组合遗传效应对C/D比值的影响发生变化。
For living donor liver transplantation, the genetic association of CYP3A5 genotype of recipient's native intestine and donor's liver allograft with tacrolimus pharmacokinetics has not been explained completely considering liver regeneration time. The goal of study was to investigate the longitudinal effects of recipient-donor combinational CYP3A5 genotypes on tacrolimus dose-normalized concentration (C/D ratio) in blood. Tacrolimus blood concentrations were measured for fifty-eight Korean adult living donor liver transplant recipients on tacrolimus-based immunosuppressants during 4 years of follow-up. CYP3A5 was genotyped for both recipient and donor, and the recipient-donor combinational genetic effect on tacrolimus C/D ratios were evaluated as a function of time after adjusting for covariates including demographics and clinical variables. CYP3A5 expresser recipients grafted from CYP3A5 expresser donors consistently had the least C/D ratio throughout the entire study period, whereas CYP3A5 expresser recipients grafted from CYP3A5 nonexpresser donors had an intermediate, and CYP3A5 nonexpresser recipients grafted from CYP3A5 nonexpresser donors had the largest C/D ratio (all p < 0.01). The CYP3A5 nonexpresser recipients grafted from CYP3A5 expresser donors showed a significant decrease from the largest to the intermediate in C/D ratio for the first month. CYP3A5 genotypes of both recipient and donor were important factors influencing pharmacokinetic variability of tacrolimus. The recipient-donor combinational genetic effect on C/D ratio changed over time after transplantation.