Influence of CYP3A4, CYP3A5 and MDR-1 polymorphisms on tacrolimus pharmacokinetics and early renal dysfunction in liver transplant recipients
Influence of CYP3A4, CYP3A5 and MDR-1 polymorphisms on tacrolimus pharmacokinetics and early renal dysfunction in liver transplant recipients
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CYP3A4、CYP3A5 和 MDR-1 多态性对肝移植受者他克莫司药代动力学和早期肾功能障碍的影响。
DOI：
10.1016/j.gene.2012.10.048
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发表时间：
2013-01-10
期刊：
影响因子：
3.5
通讯作者：
Wang, Lanlan
中科院分区：
文献类型：
--
作者：
Shi, Yunying;Li, Yi;Wang, Lanlan
**目的**：他克莫司是器官移植中广泛使用的一种免疫抑制药物。他克莫司的口服生物利用度在个体间差异很大，且在很大程度上取决于细胞色素P450 3A（CYP3A）亚家族和P - 糖蛋白（P - gp）的活性。近期研究表明，CYP3A亚家族和P - gp（MDR - 1）的单核苷酸多态性（SNPs）对肝移植受者可能产生影响，这是影响他克莫司药代动力学以及他克莫司所致肾损伤的最重要变量之一。
**方法**：本研究共纳入216名肝移植受者。受者的平均随访时间为52个月（范围16至96个月）。所有肝移植受者均处于稳定期，血清肌酐（SCr）正常。对所有接受他克莫司治疗的肝移植受者，采用高分辨率熔解曲线分析（HRM分析）对CYP3A5（6986A＞G）、CYP3A4内含子6（CYP3A4*22）、MDR - 1外显子26（3435C＞T）和外显子12（1236 C＞T）的单核苷酸多态性进行基因分型。通过尿液中不同微量蛋白（包括微量白蛋白（MA）、尿免疫球蛋白G（IGU）、尿转铁蛋白（TRU）和α1 - 微球蛋白（A1M））的升高，将受者定义为早期肾损伤。
**结果**：CYP3A5*1/*1（AA）基因型受者的他克莫司日剂量高于CYP3A5*3/*3（GG）基因型受者[3.0（2.0 - 4.0）对比2.0（1.5 - 2.5）mg/d，P＜0.05]。CYP3A5基因多态性影响他克莫司的日剂量需求、血药浓度和肾毒性。移植前对这种单核苷酸多态性进行筛查，可能有助于选择合适的初始日剂量，并实现理想的免疫抑制效果。（c）2012爱思唯尔出版社。保留所有权利。
Objectives: Tacrolimus is a widely used immunosuppressive drug in organ transplantation. The oral bioavailability of tacrolimus varies greatly between individuals and depends largely on the activity of both the cytochrome P450 3A (CYP3A) subfamily and P-glycoprotein (P-gp). The possible influence of single nucleotide polymorphisms (SNPs) of CYP3A subfamily and P-gp (MDR-1) in liver transplant recipients has recently been indicated as one of the most important variables affecting the pharmacokinetics of tacrolimus and the renal injury induced by tacrolimus.Methods: A total of 216 liver transplant recipients were enrolled in this study. The recipients' mean follow-up time was 52 mo (range from 16 to 96 mo). All liver transplant recipients were all in a stable stage with normal serum creatinine (SCr). All liver transplant recipients treated with tacrolimus were genotyped for CYP3A5 (6986A>G), CYP3A4 intron 6 (CYP3A4*22), MDR-1 exon 26 (3435C>T) and exon 12 (1236 C>T) SNPs by HRM analysis (high-resolution melting curve analysis). Recipients were defined as the early renal injury by the elevation of different microproteins in the urine including microalbumin (MA), urine immunoglobulin G (IGU), urine transferrin (TRU) and alpha 1-microglobulin (A1M).Results: The daily dose of tacrolimus was higher for recipients with CYP3A5*1/*1 (AA) genotype than those with CYP3A5*3/*3 (GG) genotype [3.0 (2.0-4.0) versus 2.0 (1.5-2.5) mg/d, PG genetic polymorphism affected daily dose requirements, concentration and nephrotoxicity of tacrolimus. Screening for this single nucleotide polymorphism before the transplantation might be helpful for the selection of adequate initial daily dose and to achieve the desired immunosuppression outcome. (c) 2012 Elsevier B.V. All rights reserved.