<span style="font-family:&quot;font-size:medium;">CYP2C19、POR、ABCC2 基因多态性与侵袭性真菌</span><span style="font-family:&quot;font-size:medium;">感染患者伏立康唑血药浓度相关性研究</span>

李雅暄, 李兴德, 王国徽, 毛盼盼, 张函舒, 鲁塞娟, 宋沧桑

doi:magtech-2025-07-11-00003

中国药物评价 >

2025 , Vol. 42 >Issue 5: 345 - 345-350

DOI: https://doi.org/magtech-2025-07-11-00003

药物研究

CYP2C19、POR、ABCC2 基因多态性与侵袭性真菌感染患者伏立康唑血药浓度相关性研究

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1.昆明医科大学附属甘美医院药学部，云南昆明 650224；
2.昆明市第一人民医院药学部，云南昆明 650224

李雅暄，女，硕士，药师，研究方向：临床药学。

收稿日期: 2025-07-11

修回日期: 2025-08-19

录用日期: 2025-11-27

网络出版日期: 2025-12-15

基金资助

云南省科技厅重大科技专项计划项目（202302AA310018-C-3）；云南省卫生健康委员会医学领军人才培养项目（L-2018012）；云南省临床药学中心建设项目；昆明市医学科技领军人才培养项目[2023-SW(领军)-04]；云南省科技厅科技计划项目（202301AY070001-112）

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Study on the Correlation Between the Gene Polymorphisms of CYP2C19， POR and ABCC2 and the Plasma Concentration of Voriconazole in Patients with Invasive Fungal Infections

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1.Kunming Medical University， Yunnan Kunming 650244， China；
2.Pharmacy Department， Kunming First People′s Hospital， Yunnan Kunming 650244， China

Received date: 2025-07-11

Revised date: 2025-08-19

Accepted date: 2025-11-27

Online published: 2025-12-15

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摘要

目的：探究侵袭性真菌感染(invasive fungal infection，IFI)患者CYP2C19、POR、ABCC2基因多态性对伏立康唑（voriconazole，VRZ）稳态血药浓度（cmin）的影响。方法：前瞻性收集IFI患者的外周血，二维液相色谱法监测伏立康唑稳态血药浓度（VRZ cmin），同时采用聚合酶链反应法检测CYP219 rs4244285、CYP219 rs4986893、POR rs10954732、ABCC2 rs717620基因多态性，分析各基因型与VRZ血药浓度的相关性。结果：研究共纳入55例IFI患者的VRZ cmin血浆样本。分析显示，CYP2C19 rs4244285位点，GG型患者的VRZ cmin值显著低于A等位基因携带者（P＜0.05）；CYP2C19 rs4986893 位点，GG型患者的VRZ cmin值明显低于A等位基因携带者（P＜0.05）；ABCC2 rs717620 位点，CC型患者的VRZ cmin值显著低于T等位基因携带者（P＜0.05）；POR rs10954732位点与IFI患者的VRZ cmin值之间未呈现出显著的相关性（P＞0.05）；CYP2C19不同代谢分布IFI患者的VRZ cmin存在显著差异（P<0.01）；以CYP2C19代谢分布分层后，POR rs10954732和ABCC2 rs717620基因多态性对IFI患者VRZ cmin的影响无显著统计学差异。结论：ABCC2 rs717620的T等位基因携带者可使VRZ血药浓度增加；CYP2C19代谢分布中，PMs患者的VRZ cmin高于EMs、IMs患者；CYP2C19代谢分布分型后POR rs10954732和ABCC2 rs717620基因多态性对IFI患者VRZ cmin无影响。

关键词： ; font-size:medium; ">伏立康唑；侵袭性真菌感染；CYP2C19；POR；ABCC2；基因多态性；血药浓度

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李雅暄, 李兴德, 王国徽, 毛盼盼, 张函舒, 鲁塞娟, 宋沧桑 . CYP2C19、POR、ABCC2 基因多态性与侵袭性真菌感染患者伏立康唑血药浓度相关性研究[J]. 中国药物评价, 2025 , 42(5) : 345 -345-350 . DOI: magtech-2025-07-11-00003

Abstract

Objective： To investigate the impact of genetic polymorphisms of CYP2C19， POR， and ABCC2 on the trough plasma concentration (cmin) of voriconazole (VRZ) in patients with invasive fungal infection (IFI). Methods： Peripheral blood samples from IFI patients were prospectively collected. The plasma concentration of VRZ was determined using two-dimensional liquid chromatography. Simultaneously， polymerase chain reaction was employed to detect the genetic polymorphisms of CYP219 rs4244285， CYP219 rs4986893， POR rs10954732， and ABCC2 rs717620. The correlation between each genotype and the VRZ plasma concentration was then analyzed. Results： A total of 55 plasma samples of the steady-state trough plasma concentration of voriconazole in IFI patients were enrolled in this study. The analysis revealed that at the CYP2C19 rs4244285 locus， the VRZ cmin value in patients with the GG genotype was significantly lower than that in A allele carriers (P<0.05). Similarly， at the CYP2C19 rs4986893 locus， the VRZ cmin value in patients with the GG genotype was markedly lower than that in A allele carriers (P<0.05). At the ABCC2 rs717620 locus， the VRZ cmin value in patients with the CC genotype was significantly lower than that in T allele carriers (P<0.05). However， no significant correlation was observed between the POR rs10954732 locus and the VRZ cmin value in IFI patients (P>0.05). There were significant differences in VRZ cmin among IFI patients with different CYP2C19 metabolic distributions (P<0.01). After stratification based on CYP2C19 metabolic distribution， the influence of the genetic polymorphisms of POR rs10954732 and ABCC2 rs717620 on VRZ cmin in IFI patients did not reach statistical significance. Conclusions： Carriers of the T allele of ABCC2 rs717620 can increase the plasma concentration of VRZ. In the metabolic distribution of CYP2C19， the minimum steady-state concentration of VRZ in PMs patients is higher than that in EMs and IMs patients. After classifying the metabolic distribution of CYP2C19， the gene polymorphisms of POR rs10954732 and ABCC2 rs717620 have no effect on the VRZ cmin in patients with invasive fungal infection.

Key words： ; font-size:medium; ">Voriconazole； Invasive fungal infection； CYP2C19； POR； ABCC2； Genetic polymorphism； Plasma concentration

参考文献

[1] Sanguinetti M， Posteraro B， Beigelman-Aubry C， et al. Diagnosis and treatment of invasive fungal infections： looking ahead [J]. J Antimicrob Chemother， 2019， 74(Suppl 2)： ii27-ii37.
     [2] Natesan SK， Chandrasekar PH. Isavuconazole for the treatment of invasive aspergillosis and mucormycosis： current evidence， safety， efficacy， and clinical recommendations [J]. Infection Drug Resistance， 2016， 9： 291-300.
     [3] 血液病/恶性肿瘤患者侵袭性真菌病的诊断标准与治疗原则(第五次修订版)[J]. 临床医学研究与实践，2017，2(20)：201.
     [4] 毛盼盼，杜一民，张阳，等.伏立康唑预防HSCT术后侵袭性真菌感染疗效及安全性的Meta分析[J]. 大理大学学报，2017，2(2)：31-36.
     [5] Takesue Y， Hanai Y， Oda K， et al. Clinical practice guideline for the therapeutic drug monitoring of voriconazole in non-Asian and Asian adult patients： consensus review by the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring [J]. Clin Ther， 2022， 44(12)： 1604-1623.
     [6] Moriyama B， Obeng AO， Barbarino J， et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP2C19 and voriconazole therapy [J]. Clin Pharmacol Ther， 2017， 102(1)： 45-51.
     [7] Chen K， Zhang X， Ke X， et al. Individualized medication of voriconazole： a practice guideline of the division of therapeutic drug monitoring， Chinese pharmacological society [J]. Therapeutic Drug Monitoring， 2018， 40(6)： 663-674.
     [8] 周丽娟，桑智慧，李慧红，等.CYP2C19基因多态性联合C-反应蛋白指导伏立康唑在血液病患者合并侵袭性真菌感染防治中的应用[J]. 中国新药杂志，2024，33(22)：2352-2358.
     [9] Berge M， Guillemain R， Trégouet DA， et al. Effect of cytochrome P450 2C19 genotype on voriconazole exposure in cystic fibrosis lung transplant patients [J]. European J Clin Pharmacol， 2011， 67(3)： 253-260.
     [10] Wang T， Zhu H， Sun J， et al. Efficacy and safety of voriconazole and CYP2C19 polymorphism for optimised dosage regimens in patients with invasive fungal infections [J]. Intern J Antimicrobial Agents， 2014， 44(5)： 436-42.
     [11] Shirasaka Y， Chaudhry AS， McDonald M， et al. Interindividual variability of CYP2C19-catalyzed drug metabolism due to differences in gene diplotypes and cytochrome P450 oxidoreductase content [J]. Pharmacogenomics J， 2016， 16(4)： 375-387.
     [12] Dermauw W， Van Leeuwen T. The ABC gene family in arthropods： comparative genomics and role in insecticide transport and resistance [J]. Insect Biochemistry Molecular Biol， 2014， 45： 89-110.
     [13] 李雅暄，李兴德，王国徽，等.基因多态性对侵袭性真菌感染患者伏立康唑血药浓度影响的Meta分析[J]. 中国药房，2025，36(2)：225-231.
     [14] Shi Y， Xiang P， Li L， et al. Analysis of 50 SNPs in CYP2D6， CYP2C19， CYP2C9， CYP3A4 and CYP1A2 by MALDI-TOF mass spectrometry in Chinese Han population [J]. Forensic Science Intern， 2011， 207(1-3)： 183-187.
     [15] Zeng G， Wang L， Shi L， et al. Variability of voriconazole concentrations in patients with hematopoietic stem cell transplantation and hematological malignancies： influence of loading dose， procalcitonin， and pregnane X receptor polymorphisms [J]. European J Clin Pharmacol， 2020， 76(4)： 515-523.
     [16] Chen L， Zheng C， Hao M， et al. Association of ABCC2 polymorphism with clopidogrel response in Chinese patients undergoing percutaneous coronary intervention [J]. Front Pharmacol， 2022， 13：889473.
     [17] Allegra S， Fatiguso G， De Francia S， et al. Pharmacogenetic of voriconazole antifungal agent in pediatric patients [J]. Pharmacogenomics， 2018， 19(11)： 913-925.
     [18] Zeng G， Shi L， Li H， et al. Effect of cyclosporine a and polymorphisms in CYP2C19 and ABCC2 on the concentration of voriconazole in patients undergoing allogeneic hematopoietic stem cell transplantation [J]. Xenobiotica， 2020， 50(5)： 614-619.
     [19] 王霖霖. 药物基因组学与肾功能对伏立康唑稳态谷浓度的影响研究 [D]. 中南大学， 2024.

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