Population pharmacokinetic and pharmacogenomic analysis of tacrolimus in pediatric living-donor liver transplant recipients
Population pharmacokinetic and pharmacogenomic analysis of tacrolimus in pediatric living-donor liver transplant recipients
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DOI：
10.1016/j.clpt.2006.06.008
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发表时间：
2006-10-01
影响因子：
6.7
通讯作者：
Inui, Ken-ichi
中科院分区：
文献类型：
--
作者：
Fukudo, Masahide;Yano, Ikuko;Inui, Ken-ichi
目的：我们的目的是研究他克莫司在儿童活体肝移植受者中的群体药代动力学，并检测多药耐药1（MDR1）基因和细胞色素P450（CYP3A4和CYP3A5）基因对他克莫司口服清除率的影响。回顾性收集了130例在术后前50天内接受他克莫司治疗的新生儿肝移植受者的数据。药物基因组学数据，包括CYP3A5 * 3多态性和信使核糖核酸（mRNA）的表达水平的MDR 1，CYP3A4，CYP3A5在天然肠和移植肝移植的65个收件人。采用非线性混合效应模型程序NONMEM进行群体药代动力学分析，估计群体平均表观清除率（CL/F）和表观分布容积（V/F）参数。CL/F和V/F均与体重呈异速生长相关，CL/F随AST值升高而降低。CL/F在术后即刻呈线性增加，但在术后第21天后不随时间变化。肠MDR1 mRNA水平显著影响初始CL/F（P <0.005）。此外，携带CYP3A5 * 1的移植肝受者的CL/F随时间的增加比携带CYP3A5 * 3/* 3基因型的患者高2倍（95%置信区间，1.19 - 2.81倍; P <0.005）。贝叶斯法预测他克莫司浓度在术后任何一天均无明显偏倚，移植后前2周的平均绝对预测误差低于3 ng/mL。移植肝中肠上皮细胞MDR1 mRNA水平和CYP3A5 * 1等位基因对活体肝移植后他克莫司口服清除率的个体间差异有不同的贡献。
Objective: Our objective was to investigate the population pharmacokinetics of tacrolimus in pediatric living-donor liver transplant recipients and examine the effects of the multidrug resistance 1 (MDR1) gene and the cytochrome P450 (CYP) genes CYP3A4 and CYP3A5 on the oral clearance of tacrolimus.Methods. Data were collected retrospectively from 130 de novo pediatric liver transplant recipients treated with tacrolimus during the first 50 postoperative days. Pharmacogenomic data including both the CYP3A5*3 polymorphism and messenger ribonucleic acid (mRNA) expression levels of MDR1, CYP3A4, and CYP3A5 in the native intestine and the graft liver at transplantation were obtained from 65 of the recipients. Population pharmacokinetic analysis was performed with the nonlinear mixed-effects modeling program NONMEM to estimate population mean parameters of apparent clearance (CL/F) and apparent volume of distribution (V/F).Results. Both CL/F and V/F were allometrically related to body weight, and CL/F decreased when the AST value was elevated. CL/F increased linearly in the immediate postoperative period but did not change with time after postoperative day 21. The intestinal MDR1 mRNA level significantly influenced the initial CL/F (P < .005). Furthermore, the increase in CL/F over time was 2 times higher (95% confidence interval, 1.19-2.81 times; P < .005) in recipients of a CYP3A5*1-carrying graft liver than in patients with the hepatic CYP3A5*3/*3 genotype. The Bayesian prediction for tacrolimus concentrations was not significantly biased on any postoperative day, and the mean absolute prediction error was lower than 3 ng/mL after the first 2 weeks of transplantation.Conclusions. The enterocyte MDR1 mRNA level and the CYP3A5*1 allele in the graft liver contribute differently to the interindividual variability in the oral clearance of tacrolimus after living-donor liver transplantation.