Fukudo M, Yano I, Masuda S, Goto M, Uesugi M, Katsura T, Ogura Y, Oike F, Takada Y, Egawa H, Uemoto S, Inui K.
药剂科，药学系，京都大学附属医院，京都大学，京都，日本
目标：我们的目标是探讨他克莫司在小儿活体肝移植受体中的群体药动学，多重耐药1 (MDR1)基因和细胞色素P450（CYP）基因中的CYP3A4和CYP3A5对口服他克莫司的代谢清除率的影响。
方法：我们前瞻性的收集了130例de novo小儿肝移植受体的资料，这些患者在肝移植术后的前50天均使用他克莫司治疗。我们从65名小儿肝移植移植受体的案例中获得了药物基因数据，包括移植中原小肠和移植肝的CYP3A5*3基因型多态性和MDR1、CYP3A4和CYP3A5的信使RNA（mRNA）表达。通过群体药动学分析法和非线性混合效应模型计划（NONMEM）来评估表观清除率（CL/F）和表观分布容积(V/F)的群体平均参数。
结果：CL/F和V/F与体重有密切关系，当天冬氨酸转氨酶（AST）值上升时，CL/F降低。CL/F在手术后立即呈线性增加，但是从术后第21天开始就不再随时间而变化了。肠道中的MDR1 mRNA水平显著影响初始CL/F (P < .005)。此外，随着时间的增加，CYP3A5*1移植肝受体中的CL/F值是CYP3A5*3/*3基因型的两倍(置信区间95%, 1.19-2.81倍; P < 0.005)。他克莫司浓度的贝叶斯预测没有明显偏袒术后的任何一天，移植术后前两周绝对预测误差的平均值低于3 ng/ml。
结论：移植肝的肠上皮细胞MDR1 mRNA水平与CYP3A5*1等位基因对活体肝移植术后他克莫司口服耐受性个体差异的影响是不同的。
Clin Pharmacol Ther. 2006 Oct;80(4):331-45.
Population pharmacokinetic and pharmacogenomic analysis of tacrolimus in pediatric living-donor liver transplant recipients
Fukudo M, Yano I, Masuda S, Goto M, Uesugi M, Katsura T, Ogura Y, Oike F, Takada Y, Egawa H, Uemoto S, Inui K.
Department of Pharmacy, Faculty of Medicine, Kyoto University Hospital, Kyoto University, Kyoto, Japan.
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 < 0.005) 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.
PMID: 17015051 [PubMed - indexed for MEDLINE]
PMID: 17015051 [PubMed - indexed for MEDLINE]
[责任编辑:刘 聪]
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