Effects of CYP2C19, CYP2C9 and CYP3A4 gene polymorphisms on plasma voriconazole levels in Chinese pediatric patients.

IF 1.7 3区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Pharmacogenetics and genomics Pub Date : 2022-06-01 DOI:10.1097/FPC.0000000000000464

Xinghua Fan, Hong Zhang, Zhipeng Wen, Xiaoli Zheng, Yi Yang, Jihong Yang

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引用次数: 4

Abstract

Objectives: Voriconazole is the most commonly used antifungal agent in clinical application. Previous studies suggested that voriconazole was extensively metabolized by CYP450 enzyme system, including CYP2C19, CYP2C9 and CYP3A4, which contributed to the individual variability of the pharmacokinetic process of voriconazole. This study aimed to investigate the effects of CYP2C19, CYP2C9 and CYP3A4 gene polymorphisms on plasma voriconazole concentrations in Chinese pediatric patients.

Methods: This study prospectively evaluated pediatric patients administrating voriconazole for the treatment or prophylaxis of invasive fungal infections from October 2018 to July 2020. Seven single-nucleotide polymorphisms in CYP2C19 (CYP2C19*2, CYP2C19*3, and CYP2C19*17), CYP2C9 (CYP2C9*3, CYP2C9*13) and CYP3A4 (CYP3A4*22, rs4646437) were detected by real-time fluorescent PCR with TaqMan probes. The voriconazole trough plasma concentration was determined by UPLC-MS/MS.

Results: A total of 68 pediatric patients were enrolled in this study. Our results showed that voriconazole plasma concentrations of patients with CYP2C19*2 or CYP2C19*3 allele were significantly higher than that with wild-type carriers (P < 0.0001, P = 0.004, respectively). However, CYP2C9*3 and CYP3A4 rs4646437 were not significantly associated with voriconazole plasma levels. The CYP2C19*17, CYP2C9*13 and CYP3A4*22 alleles were not observed in our study. Additionally, multiple linear regression analysis indicated that CYP2C19*2 and CYP2C19*3 alleles remained predictors of voriconazole plasma concentration (r2 = 0.428; P < 0.0001). For CYP2C19 metabolizer phenotype, trough concentration of voriconazole was significantly lower in NM group compared with IM (P < 0.0001) and PM (P = 0.004) groups.

Conclusion: Voriconazole plasma levels in pediatric patients are mainly affected by CYP2C19 gene polymorphisms.

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CYP2C19、CYP2C9和CYP3A4基因多态性对我国儿科患者血浆伏立康唑水平的影响

目的:伏立康唑是临床应用最广泛的抗真菌药物。既往研究表明，伏立康唑被CYP450酶系统广泛代谢，包括CYP2C19、CYP2C9和CYP3A4，这导致了伏立康唑药代动力学过程的个体差异性。本研究旨在探讨CYP2C19、CYP2C9和CYP3A4基因多态性对我国儿科患者血浆伏立康唑浓度的影响。方法:本研究对2018年10月至2020年7月使用伏立康唑治疗或预防侵袭性真菌感染的儿科患者进行前瞻性评估。采用TaqMan探针实时荧光PCR检测CYP2C19 (CYP2C19*2、CYP2C19*3、CYP2C19*17)、CYP2C9 (CYP2C9*3、CYP2C9*13)、CYP3A4 (CYP3A4*22、rs4646437)基因的7个单核苷酸多态性。采用UPLC-MS/MS法测定伏立康唑谷血药浓度。结果:本研究共纳入68例儿科患者。结果显示，CYP2C19*2、CYP2C19*3等位基因患者的伏立康唑血药浓度显著高于野生型携带者(P < 0.0001, P = 0.004)。而CYP2C9*3和CYP3A4 rs4646437与伏立康唑血浆水平无显著相关性。本研究未发现CYP2C19*17、CYP2C9*13和CYP3A4*22等位基因。多元线性回归分析显示，CYP2C19*2和CYP2C19*3等位基因仍是伏立康唑血药浓度的预测因子(r2 = 0.428;P < 0.0001)。对于CYP2C19代谢物表型，NM组伏立康唑谷浓度显著低于IM组(P < 0.0001)和PM组(P = 0.004)。结论:小儿患者伏立康唑血浆水平主要受CYP2C19基因多态性的影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Pharmacogenetics and genomics 医学-生物工程与应用微生物

CiteScore

3.20

自引率

3.80%

发文量

审稿时长

3 months

期刊介绍： Pharmacogenetics and Genomics is devoted to the rapid publication of research papers, brief review articles and short communications on genetic determinants in response to drugs and other chemicals in humans and animals. The Journal brings together papers from the entire spectrum of biomedical research and science, including biochemistry, bioinformatics, clinical pharmacology, clinical pharmacy, epidemiology, genetics, genomics, molecular biology, pharmacology, pharmaceutical sciences, and toxicology. Under a single cover, the Journal provides a forum for all aspects of the genetics and genomics of host response to exogenous chemicals: from the gene to the clinic.