Institute of Enzymology, Research Centre for Natural Sciences, Magyar tudósok 2, Budapest, 1117, Hungary.
Heart and Vascular Center, Semmelweis University, Városmajor 68, Budapest, 1122, Hungary.
Sci Rep. 2021 Nov 1;11(1):21389. doi: 10.1038/s41598-021-00942-y.
High inter-individual variability in tacrolimus clearance is attributed to genetic polymorphisms of CYP3A enzymes. However, due to CYP3A phenoconversion induced by non-genetic factors, continuous changes in tacrolimus-metabolizing capacity entail frequent dose-refinement for optimal immunosuppression. In heart transplant recipients, the contribution of patients' CYP3A-status (CYP3A5 genotype and CYP3A4 expression) to tacrolimus blood concentration and dose-requirement was evaluated in the early and late post-operative period. In low CYP3A4 expressers carrying CYP3A53/3, the dose-corrected tacrolimus level was significantly higher than in normal CYP3A4 expressers or in those with CYP3A51. Modification of the initial tacrolimus dose was required for all patients: dose reduction by 20% for low CYP3A4 expressers, a 40% increase for normal expressers and a 2.4-fold increase for CYP3A51 carriers. The perioperative high-dose corticosteroid therapy was assumed to ameliorate the low initial tacrolimus-metabolizing capacity during the first month. The fluctuation of CYP3A4 expression and tacrolimus blood concentration (C/D) was found to be associated with tapering and cessation of corticosteroid in CYP3A5 non-expressers, but not in those carrying CYP3A5*1. Although monitoring of tacrolimus blood concentration cannot be omitted, assaying recipients' CYP3A-status can guide optimization of the initial tacrolimus dose, and can facilitate personalized tacrolimus therapy during steroid withdrawal in the late post-operative period.
他克莫司清除率的个体间差异很大，这归因于 CYP3A 酶的遗传多态性。然而，由于非遗传因素引起的 CYP3A 表型转化，他克莫司代谢能力的持续变化需要频繁调整剂量以达到最佳免疫抑制效果。在心脏移植受者中，评估了 CYP3A 状态（CYP3A5 基因型和 CYP3A4 表达）对术后早期和晚期他克莫司血药浓度和剂量需求的影响。在携带 CYP3A53/3 的低 CYP3A4 表达者中，校正剂量的他克莫司水平明显高于正常 CYP3A4 表达者或 CYP3A51 携带者。所有患者均需要调整初始他克莫司剂量：低 CYP3A4 表达者减少 20%，正常表达者增加 40%，CYP3A51 携带者增加 2.4 倍。假设围手术期大剂量皮质类固醇治疗可以改善术后第一个月初始他克莫司代谢能力低下的情况。发现 CYP3A4 表达和他克莫司血药浓度（C/D）的波动与 CYP3A5 无表达者皮质类固醇减量和停药有关，但与携带 CYP3A5*1 者无关。尽管不能省略他克莫司血药浓度监测，但检测受者的 CYP3A 状态可以指导初始他克莫司剂量的优化，并在术后晚期皮质类固醇停药期间促进个体化他克莫司治疗。
