Fan Junwei, Wen Peihao, Yuan Liyun, Xia Yan, Hu Shijie, Zhang Xiaoqing, Peng Zhihai
Department of General Surgery, Shidong Hospital Affiliated to University of Shanghai for Science and Technology, Shanghai, China.
Department of General Surgery, Shanghai General Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China.
Front Pharmacol. 2025 Jul 21;16:1614753. doi: 10.3389/fphar.2025.1614753. eCollection 2025.
Classification system of tacrolimus elimination and its clinical significance has not been well described in liver transplantation. This study aimed to present a novel tacrolimus clearance clinical-FIS (Fast-Intermediate-Slow) classification and its gene prediction system.
Patients from 3 transplant centers were enrolled in this study. All recipients and their corresponding donor livers from center 1 were genotyped using an Affymetrix DMET Plus microarray, and association analysis was performed using trough blood concentration/weight-adjusted-dose ratios (CDR, (ng/mL)/(mg/kg)). The candidate-associated loci were then sequenced in center 2 and center 3 patients for verification.
A clinical classification based on tacrolimus CDR can effectively divide liver transplantation patients into fast elimination (FE), intermediate elimination (IE), and slow elimination (SE) groups, which we called the clinical-FIS classification. Trough blood concentrations in the clinical-SE group during the early postoperative period were higher than those in the clinical-FE and clinical-IE groups, which could lead to delayed recovery of liver (P = 0.0373) and kidney function (P = 0.0135) and a higher infection rate (P = 0.0086). The prediction accuracy of the current CPIC (Clinical Pharmacogenetics Implementation Consortium)-EIP metabolizer classification based on recipient CYP3A5 rs776746 genotype for clinical-FIS classification was only 35.56%. A newly established genetic-EIP classification including major effect genetic factors (donor and recipient CYP3A5 rs776746) and minor effect genetic factors (recipient SULT1E1 rs3775770 and donor SLC7A8 rs7141505) showed 73.2% overall consistency with the former clinical FIS classification.
Our study presented a novel tacrolimus clearance classification, clinical-FIS, and then proposed a novel prospective genetic-EIP classification as a genotyping basis for precisely predicting the clinical-FIS.
在肝移植中，他克莫司消除的分类系统及其临床意义尚未得到充分描述。本研究旨在提出一种新的他克莫司清除临床-FIS（快速-中间-缓慢）分类及其基因预测系统。
本研究纳入了来自3个移植中心的患者。使用Affymetrix DMET Plus微阵列对中心1的所有受者及其相应的供肝进行基因分型，并使用谷血药浓度/体重校正剂量比（CDR，(ng/mL)/(mg/kg)）进行关联分析。然后在中心2和中心3的患者中对候选相关位点进行测序以进行验证。
基于他克莫司CDR的临床分类可有效地将肝移植患者分为快速消除（FE）、中间消除（IE）和缓慢消除（SE）组，我们称之为临床-FIS分类。临床-SE组术后早期的谷血药浓度高于临床-FE组和临床-IE组，这可能导致肝功能（P = 0.0373）和肾功能（P = 0.0135）恢复延迟以及感染率更高（P = 0.0086）。基于受者CYP3A5 rs776746基因型的当前CPIC（临床药物基因组学实施联盟）-EIP代谢型分类对临床-FIS分类的预测准确率仅为35.56%。新建立的包括主要效应基因因素（供者和受者CYP3A rs776746）和次要效应基因因素（受者SULT1E1 rs3775770和供者SLC7A8 rs7141505）的基因-EIP分类与先前的临床FIS分类总体一致性为73.2%。
我们的研究提出了一种新的他克莫司清除分类，即临床-FIS，然后提出了一种新的前瞻性基因-EIP分类作为精确预测临床-FIS的基因分型基础。
