Investigation of CYP 3A5 and ABCB1 gene polymorphisms in the long-term following renal transplantation: Effects on tacrolimus exposure and kidney function
Investigation of CYP 3A5 and ABCB1 gene polymorphisms in the long-term following renal transplantation: Effects on tacrolimus exposure and kidney function
复制标题
DOI：
10.3892/etm.2015.2598
复制
发表时间：
2015-09-01
影响因子：
2.7
通讯作者：
Velickovic-Radovanovic, Radmila M.
中科院分区：
文献类型：
--
作者：
Stefanovic, Nikola Z.;Cvetkovic, Tatjana P.;Velickovic-Radovanovic, Radmila M.
他克莫司（Tac）的临床使用因其药代动力学的个体间差异较大以及对肾功能的慢性不良反应而变得复杂。本研究的主要目的是评估细胞色素P450 3A 5（CYP 3A 5）和ATP结合盒转运蛋白B1（ABCB 1）基因多态性对肾移植术后不同长期阶段Tac剂量需求和剂量调整浓度的潜在影响。另一个目的是研究这些多态性是否影响移植后期的肾功能。共有91例肾移植受者入选进行基因分型分析，其中53例进入药代动力学-药物遗传学研究。等位基因特异性聚合酶链反应用于ABCB 1和AB 3A 5的多态性测定。在移植后6个月、12个月和24个月，分析了与患者基因型相关的药代动力学数据（剂量、谷浓度和剂量调整的Tac浓度）和肾功能参数[肌酐（Cre）清除率和血清Cre水平]。此外，进行线性回归分析，以评估TA 13 A5和ABCB 1基因型对Tac暴露和肾功能的影响，直至移植后24个月。在肾移植后6、12和24个月，携带β 3A 5 *1/*3基因型的个体比携带β 3A 5 *3/*3基因型的个体具有更高的Tac剂量需求。结果表明，ABCB 1基因多态性并没有独立影响Tac剂量需求。回归分析显示，在移植后24个月内，β 3A 5影响Tac剂量调整浓度以及肾功能。这些发现证实，TA 3A 5多态性是肾移植后晚期Tac剂量和暴露的最重要决定因素。此外，所获得的结果表明，在肾移植后的长期时间内，肾功能的下降可能在具有β 3A 5 *1的患者中更明显。
The clinical use of tacrolimus (Tac) is complicated by the large inter-individual variability in its pharmacokinetics as well as by chronic adverse effects on renal function. The main goal of this study was to evaluate the potential influence of cytochrome P450 3A5 (CYP 3A5) and ATP-binding cassette transporter B1 (ABCB1) gene polymorphisms on Tac dose requirements and dose-adjusted concentrations in different long-term periods following renal transplantation. Another aim was to investigate whether these polymorphisms affect renal function in late post-transplant period. A total of 91 renal transplant recipients were enrolled for genotyping analysis, and 53 of these entered into a pharmacokinetic-pharmacogenetic study. Allele-specific polymerase chain reaction was used for CYP 3A5 and ABCB1 polymorphism determination. Pharmacokinetic data (dose, trough concentration and dose-adjusted concentration of Tac) and renal function parameters [creatinine (Cre) clearance and serum Cre level] were analyzed in relation to patient genotype at 6, 12 and 24 months after transplantation. Also, linear regression analysis was performed to evaluate the effect of CYP 3A5 and ABCB1 genotypes on Tac exposure and renal function up to 24 months post-transplant. Individuals carrying the CYP 3A5*1/*3 genotype had higher Tac dose requirements than CYP 3A5*3/*3 carriers at 6, 12 and 24 months after renal transplantation. The results revealed that ABCB1 polymorphism did not influence Tac dose requirements independently. Regression analysis showed that CYP 3A5 influenced the Tac dose-adjusted concentration as well as renal function up to 24 months post-transplant. These findings confirmed that CYP 3A5 polymorphism represents the most important determinant of Tac dose and exposure in the late period following renal transplantation. Furthermore, the obtained results indicate that the decline in renal function may be more pronounced in patients with CYP 3A5*1 in the long-term period after renal transplantation.