Li D, Lu W, Zhu J-Y, Gao J, Lou Y-Q, Zhang G-L
Department of Pharmacology, Basic Medical School, Health Science Centre, Beijing (Peking) University, Beijing, China.
J Clin Pharm Ther. 2007 Oct;32(5):505-15. doi: 10.1111/j.1365-2710.2007.00850.x.
Tacrolimus, an immunosuppressant widely used after liver transplantation, is characterized by a large inter-individual variability in its pharmacokinetics. The aim of this study was to perform population pharmacokinetic analysis of oral tacrolimus in liver transplant recipients and clarify the potential role of CYP3A5, MDR1 and IL-10 genetic polymorphisms in the variability of population pharmacokinetic parameters.
Tacrolimus blood concentration data (n = 1106) were collected from 104 full liver transplant patients and were analysed using a non-linear mixed-effects modelling program (nonmem). The CYP3A5*3, MDR1 G2677T/A and C3435T genetic polymorphisms were determined using polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis. The IL-10 G-1082A variant was studied by allele-specific PCR method.
The liver function in patients as indicated by the total bilirubin level (TBIL) and different CYP3A5*3 genotypes in donors (CYPD) and recipients (CYPR) were observed to influence tacrolimus pharmacokinetic parameter of apparent clearance (Cl/F). The final regression model can be expressed as Cl/F = 15.9 - 1.88 TBIL + 7.65 CYPD + 7.00 CYPR. The relative standard errors (%RSE) of the parameter estimation were lower than 30% and the residual variability of tacrolimus trough blood concentration was 2.81 ng/mL. No significant effect of MDR1 and IL-10 polymorphisms was observed on population pharmacokinetic parameter of tacrolimus within 175 days after liver transplantation.
The TBIL in patients and CYP3A5*3 genetic polymorphism in both donors and recipients contribute to the inter-individual variability of oral tacrolimus apparent clearance in Chinese adult liver transplant patients.
他克莫司是肝移植后广泛使用的一种免疫抑制剂，其药代动力学存在较大的个体间差异。本研究旨在对肝移植受者口服他克莫司进行群体药代动力学分析，并阐明CYP3A5、MDR1和IL-10基因多态性在群体药代动力学参数变异性中的潜在作用。
收集104例全肝移植患者的他克莫司血药浓度数据（n = 1106），并使用非线性混合效应建模程序（nonmem）进行分析。采用聚合酶链反应（PCR）-限制性片段长度多态性分析确定CYP3A5*3、MDR1 G2677T/A和C3435T基因多态性。通过等位基因特异性PCR方法研究IL-10 G-1082A变异。
观察到患者的肝功能指标总胆红素水平（TBIL）以及供体（CYPD）和受体（CYPR）中不同的CYP3A5*3基因型会影响他克莫司的表观清除率（Cl/F）药代动力学参数。最终回归模型可表示为Cl/F = 15.9 - 1.88TBIL + 7.65CYPD + 7.00CYPR。参数估计的相对标准误差（%RSE）低于30%，他克莫司谷血药浓度的残余变异性为2.81 ng/mL。肝移植后175天内，未观察到MDR1和IL-10基因多态性对他克莫司群体药代动力学参数有显著影响。
患者的TBIL以及供体和受体中的CYP3A5*3基因多态性导致了中国成年肝移植患者口服他克莫司表观清除率的个体间差异。
