基于CYP2C19基因多态性与治疗药物监测探讨伏立康唑与他克莫司的相互作用及不良反应  

Investigation of the interaction and adverse reactions between voriconazole and tacrolimus based on CYP2C19 gene polymorphism and therapeutic drug monitoring

作　　者：陈雪利 孙小姗 宋帅 苏涌[1,2] 夏泉 刘加涛[1,2] Chen Xueli;Sun Xiaoshan;Song Shuai;Su Yong;Xia Quan;Liu Jiatao(Dept of Pharmacy,The First Affiliated Hospital of Anhui Medical University,Hefei 230022;The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine,Hefei 230022)

机构地区：[1]安徽医科大学第一附属医院药剂科,合肥230022 [2]国家中医药管理局中药化学三级实验室,合肥230022

出　　处：《安徽医科大学学报》2024年第10期1849-1855,共7页Acta Universitatis Medicinalis Anhui

基　　金：安徽省“十三五”临床重点专科建设项目(编号:卫科教秘[2017]529号);安徽省高校优秀青年人才支持计划项目(编号:gxyq2020008);安徽医科大学2020年大学生创新创业训练计划项目(编号:S202010366010)。

摘　　要：目的根据CYP2C19基因多态性与血药浓度监测结果,分析伏立康唑(VRC)与他克莫司、环孢素等免疫抑制剂相互作用及CYP2C19基因多态性对二者相互作用和不良反应(ADR)的影响,为制定个体化VRC联合免疫抑制剂用药方案提供依据。方法采用二维液相色谱法检测VRC血药浓度,焦磷酸测序法检测患者的CYP2C19基因多态性,并同时检测合并使用的免疫抑制剂浓度。分析CYP2C19基因多态性、VRC和免疫抑制剂血药浓度及ADR的关系。结果该研究共入组61例患者,CYP2C19*2和CYP2C19*3的突变率分别为54.1%(33/61)和9.84%(6/61)。CYP2C19快代谢、中间代谢和慢代谢者的VRC血药浓度分别为(4.44±3.46)、(3.62±3.02)和(10.05±1.46)μg/ml,差异有统计学意义(P<0.05)。联用VRC后他克莫司血药浓度显著高于联用前[(13.4±9.2)ng/ml vs(6.5±3.6)ng/ml;P=0.002],且联合用药后他克莫司血药浓度随VRC浓度的升高而升高。联合使用免疫抑制剂的患者VRC浓度低于未联合免疫抑制剂的患者[(3.81±3.48)μg/ml vs(5.84±3.71)μg/ml;P=0.032)],联合使用环孢素的患者血VRC浓度显著下降(P<0.01),但联合他克莫司和吗替麦考酚对VRC血药浓度无显著影响。45.90%(28/61)的患者发生ADR,发生ADR的患者VRC浓度显著高于未发生ADR者[(7.07±3.43)μg/ml vs(3.06±2.90)μg/ml;P<0.001],且CYP2C19基因型相同的患者中有ADR者的血药浓度也高于无ADR者。结论CYP2C19基因多态性可显著影响VRC的血药浓度和ADR,VRC与他克莫司等免疫抑制剂存在显著的相互作用。CYP2C19基因多态性联合治疗药物监测可提高他克莫司和VRC个体化用药水平,并有望最大限度地降低毒性和提高治疗效果。Objective To analyze the interaction between voriconazole(VRC)and immunosuppressants such as tacrolimus and cyclosporine and the effect of CYP2C19 gene polymorphism on the interaction and adverse reactions(ADR)based on the results of CYP2C19 gene polymorphism and therapeutic drug monitoring,so as to provide a basis for the development of individualized VRC combined with immunosuppressants.Methods Two-dimensional liquid chromatography and pyrosequencing was used to detect the concentration of VRC and the CYP2C19 gene polymorphism,respectively.And the concentration of immunosuppressants was detected at the same time.The relationship among CYP2C19 gene polymorphism,the concentration of VRC and immunosuppressant and ADR was analyzed.Results A total of 61 patients were enrolled in this study,and the mutation rates of CYP2C19*2 and CYP2C19*3 were 54.1%(33/61)and 9.84%(6/61),respectively.The concentrations of VRC in patients with extensive metabolism(EMs),intermediate metabolism(IMs)and poor metabolism(PMs)were(4.44±3.46),(3.62±3.02)and(10.05±1.46)μg/ml(P<0.05),respectively.The concentration of tacrolimus after combined with VRC significantly increased compared to tacrolimus alone[(13.4±9.2)ng/ml vs(6.5±3.6)ng/ml;P=0.002],and the concentration of tacrolimus increased along with an increasing of VRC concentration.The concentration of VRC in patients combined with tacrolimus was lower than that in patients without immunosuppressants[(3.81±3.48)μg/ml vs(5.84±3.71)μg/ml;P=0.032].The concentration of VRC in patients with cyclosporine significantly decreased(P<0.01),while tacrolimus and mycophenolate mofetil had no significant effect on the concentration of VRC.45.90%(28/61)of the patients had adverse reactions,the concentration of VRC in patients with ADR was significantly higher than that in patients without ADR[(7.07±3.43)μg/ml vs(3.06±2.90)μg/ml;P<0.001].And the concentration of VRC in patients with ADR was higher than patients without ADR with based on CYP2C19 genotype.Conclusion CYP2C19 gene polymorphism c

关 键 词：CYP2C19 伏立康唑 基因多态性 免疫抑制剂 治疗药物监测 个体化治疗 二维液相色谱 

分 类 号：R453.2[医药卫生—治疗学]