Prasad Narayan, Jaiswal Akhilesh, Behera Manas Ranjan, Agarwal Vikas, Kushwaha Ravi, Bhadauria Dharmendra, Kaul Anupama, Gupta Amit
Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
Kidney Int Rep. 2019 Sep 27;5(1):28-38. doi: 10.1016/j.ekir.2019.09.013. eCollection 2020 Jan.
Tacrolimus (TAC) is the mainstay immunosuppressant for renal transplantation. A narrow therapeutic index, multiple drug interactions, and interindividual variability in pharmacokinetics make it obligatory to monitor therapeutic drug levels. The () and CYP3A5 gene polymorphism may blend to achieve the optimal level. The optimal dose as per body weight is difficult to single out in the early posttransplantation period. In this study, we aimed to analyze the melding effect of both gene polymorphisms and to elicit the dose depending on the combination of genetic single nucleotide polymorphisms (SNPs) in northern Indian transplant recipients, for whom data are limited.
The daily TAC dose, weight-adjusted doses (mg/kg per day), TAC trough blood concentration (average of at least 3 levels), dose normalized with a corresponding dose using TAC concentration/weight-adjusted dose ratio (ng/ml per mg/kg per day) of 248 patients were recorded. All recipients were genotyped for the SNPs of CYP3A5 at intron 3 A6986G (the *3 or *1 allele), at exons 12 (C1236T), 21 (G2677A/T), and 26 (C3435T). We analyzed the blending effect of mutant SNPs of the gene and CYP3A5 for optimized TAC levels.
Among CYP3A5 genotypic variants, the dose-adjusted TAC level was significantly lower, and the TAC dose required to achieve the target level was significantly higher, in CYP3A511 (expressor) than that of CYP3A513 and CYP3A533. Of the gene SNPs, only the G2677T/A homozygous mutant was significantly associated with TAC level, and it was strongly correlated with P-gp expression.The daily TAC dose requirement was highest with a combination of CYP3A511 and homozygous mutant TT+AA genotype of G2677T/A, and was lowest with CYP3A533 and wild-type GG of the G2677T/A genotype.
Both CYP gene and gene polymorphism affect TAC dose requirements, and there is a need to look for both in an individual to achieve the target trough concentration.
他克莫司（TAC）是肾移植的主要免疫抑制剂。其治疗指数窄、存在多种药物相互作用以及药代动力学的个体差异使得监测治疗药物水平成为必要。（）和CYP3A5基因多态性可能共同作用以达到最佳水平。在移植后的早期阶段，很难确定根据体重的最佳剂量。在本研究中，我们旨在分析这两种基因多态性的融合效应，并根据印度北部移植受者基因单核苷酸多态性（SNP）的组合来确定剂量，目前针对这些受者的数据有限。
记录了248例患者的每日TAC剂量、体重调整剂量（毫克/千克/天）、TAC血药谷浓度（至少3次检测结果的平均值）以及使用TAC浓度/体重调整剂量比（纳克/毫升/毫克/千克/天）进行剂量标准化后的剂量。所有受者均针对CYP3A5基因内含子3 A6986G（3或1等位基因）、外显子12（C1236T）、21（G2677A/T）和26（C3435T）的SNP进行基因分型。我们分析了（）基因和CYP3A5基因的突变SNP对优化TAC水平的融合效应。
在CYP3A5基因分型变体中，CYP3A511（表达型）的剂量调整后的TAC水平显著较低，达到目标水平所需的TAC剂量显著高于CYP3A513和CYP3A533。在（）基因SNP中，只有G2677T/A纯合突变与TAC水平显著相关，且与P-糖蛋白表达密切相关。每日TAC剂量需求在CYP3A511与G2677T/A的纯合突变TT + AA基因型组合时最高，在CYP3A533与G2677T/A基因型的野生型GG组合时最低。
CYP基因和（）基因多态性均影响TAC剂量需求，为达到目标谷浓度，有必要对个体同时进行这两种基因的检测。
