The impact of CYP3A5, NR1I2, and POR polymorphisms on tacrolimus dose-adjusted concentration and clinical outcomes in adult allogeneic haematopoietic stem cell transplantation.

IF 1.3 4区医学 Q4 PHARMACOLOGY & PHARMACY

Xenobiotica Pub Date : 2025-01-07 DOI:10.1080/00498254.2024.2448967

Yuan Gao, Jingjing Ma

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引用次数: 0

Abstract

Polymorphisms in genes related to drug-metabolising enzymes may affect tacrolimus exposure. This study aimed to assess the influence of CYP3A5, NR1I2, and POR polymorphisms on tacrolimus pharmacokinetics and outcomes in allogeneic haematopoietic stem cell transplantation (HSCT).Forty-six adult patients receiving oral tacrolimus at an initial dose of 0.03 mg/kg/day for acute graft versus host disease (GVHD) prophylaxis after allogeneic HSCT were enrolled in this retrospective study. Genetic polymorphisms were detected in relation to concentration/dose (C/D) ratios of tacrolimus and the incidence of acute GVHD and acute kidney injury (AKI).The CYP3A5 *3/*3 genotype and co-administration of voriconazole were significantly associated with increased C/D ratios of tacrolimus (p < 0.05). NR1I2 8055CC presents a significantly higher tacrolimus C/D ratio compared with carriers of 8055CT and 8055TT genotypes in allogeneic HSCT recipients with the CYP3A5*1 allele (p = 0.033). Younger age and recipients with the CYP3A5*1 allele were significantly associated with higher incidence of II-IV acute GVHD post-transplantation.CYP3A5*3, NR1I2 8055C > T, and concomitant use of voriconazole are important determinants affecting tacrolimus pharmacokinetics. Moreover, CYP3A5*1 allele and younger age are independent risk factors for II-IV acute GVHD in HSCT recipients.

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CYP3A5、NR1I2和POR多态性对成人异基因造血干细胞移植中他克莫司剂量调整浓度和临床结果的影响

1. 与药物代谢基因相关的基因多态性可能影响他克莫司暴露。本研究旨在评估CYP3A5、NR1I2和POR多态性对他克莫司药代动力学和异基因造血干细胞移植（HSCT）结果的影响。这项回顾性研究纳入了46名成年患者，他们在同种异体造血干细胞移植后接受口服他克莫司，初始剂量为0.03mg/kg/天，用于预防急性移植物抗宿主病（GVHD）。他克莫司浓度/剂量比（C/D）与急性GVHD和急性肾损伤（AKI）发生率之间存在遗传多态性。CYP3A5* 3/*3基因型和同时给药voriconazole与他克莫司C/D比值升高有显著相关性(CYP3A5*1等位基因的同种异体HSCT接受者中，P NR1I2 8055CC比8055CT和8055TT基因型携带者的他克莫司C/D比值显著升高（P = 0.033）。年龄较小和携带CYP3A5*1等位基因的受体与移植后II-IV期急性GVHD的发生率显著相关。CYP3A5*3、NR1I2 8055 C > T及合用伏立康唑是影响他克莫司药代动力学的重要因素。此外，CYP3A5*1等位基因和年龄较小是HSCT受者II-IV期急性GVHD的独立危险因素。

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来源期刊

Xenobiotica 医学-毒理学

CiteScore

3.80

自引率

5.60%

发文量

审稿时长

2 months

期刊介绍： Xenobiotica covers seven main areas, including:General Xenobiochemistry, including in vitro studies concerned with the metabolism, disposition and excretion of drugs, and other xenobiotics, as well as the structure, function and regulation of associated enzymesClinical Pharmacokinetics and Metabolism, covering the pharmacokinetics and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in manAnimal Pharmacokinetics and Metabolism, covering the pharmacokinetics, and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in animalsPharmacogenetics, defined as the identification and functional characterisation of polymorphic genes that encode xenobiotic metabolising enzymes and transporters that may result in altered enzymatic, cellular and clinical responses to xenobioticsMolecular Toxicology, concerning the mechanisms of toxicity and the study of toxicology of xenobiotics at the molecular levelXenobiotic Transporters, concerned with all aspects of the carrier proteins involved in the movement of xenobiotics into and out of cells, and their impact on pharmacokinetic behaviour in animals and manTopics in Xenobiochemistry, in the form of reviews and commentaries are primarily intended to be a critical analysis of the issue, wherein the author offers opinions on the relevance of data or of a particular experimental approach or methodology