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药物代谢相关基因多态性对难治性肾病患儿他克莫司血药浓度及安全性的影响 被引量:3

Effect of drug metabolism gene polymorphisms on blood concentration and safety of tacrolimus in children with refractory nephrotic syndrome
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摘要 目的探讨药物代谢相关基因多态性对难治性肾病综合征(RNS)患儿他克莫司(TAC)血药浓度及安全性的影响。方法研究设计为前瞻性观察性临床研究。研究基础上加用对象选自2018年9月1日至2019年8月31日在郑州大学第一附属医院儿科住院拟在糖皮质激素治疗基础上加用TAC(首次应用)的RNS患儿。患儿入组后均另行建立临床研究档案,详细记录TAC治疗6个月期间的各种临床情况。所有患儿在加用TAC第7天采集外周静脉血行TAC血药谷浓度检测,根据检测结果进行TAC剂量调整;住院期间择机采血进行三磷酸腺苷结合盒转运体B1(ABCB1)、细胞色素P450(CYP)2C19、CYP3A4、CYP3A5和核受体亚家族1组I成员2(NR1I2)基因多态性检测。将完成6个月TAC治疗和随访的患儿,根据基因型检测结果分别分为野生型组、杂合突变型组和纯合突变型组,比较不同基因型组患儿初次TAC剂量调整血药谷浓度(C/D);并分别分为突变基因携带组(杂合突变型+纯合突变型)和野生型组,比较各组患儿TAC不良反应发生率。结果纳入分析的患儿共39例,男性24例,女性15例;年龄3~13岁,中位年龄8岁。根据基因型分别分组进行TAC初次C/D比较的结果显示,CYP2C19纯合突变型(*2*2)组患儿初次TAC C/D明显高于野生型(*1*1)组[3.65(2.78,7.43)μg/L比1.53(1.27,3.33)μg/L,P=0.032],CYP3A5纯合突变型(*3*3)组患儿初次TAC C/D明显高于野生型(*1*1)组和杂合突变型(*1*3)组[3.68(3.05,5.14)μg/L比2.10(0.77,3.56)μg/L、1.74(1.47,3.25)μg/L,P=0.046,P=0.009],而CYP3A4、ABCB1和NR1I2基因不同基因型组之间TAC初次C/D差异均无统计学意义(均P>0.05)。TAC治疗6个月期间,39例患儿中有7例发生不良反应(Naranjo因果关系评估“很可能”2例,“可能”5例),其中感染4例,皮疹、高血压脑病和抽搐各1例。ABCB1突变基因(CT、TT)携带组患儿不良反应发生率明显高于野生型(CC)组患儿[30.4%(7/23)比0(0/16),P=0.033]。结论CYP2C19和CYP3A5基因多态性对TAC血药浓度有明显影响,ABCB1基因多态性对TAC安全性有明显影响,临床应给予关注。 Objective To explore the effect of drug metabolism gene polymorphisms on blood concentration and safety of tacrolimus(TAC)in children with refractory nephrotic syndrome(RNS).Methods The study was designed as prospective observational clinical study.The subjects were selected from the children with RNS who were hospitalized in Department of Pediatrics,the First Affiliated Hospital of Zhengzhou University from September 1,2018 to August 31,2019 and planned to receive TAC(first applica‑tion)at the basis of glucocorticoids treatment.Clinical research files were formed and clinical conditions within 6 months of TAC treatment were recorded in detail for all subjects.The peripheral venous blood of all children was collected on the 7th day after TAC application for TAC blood trough concentration detection,and the TAC dose was adjusted according to the results.Blood samples were collected at the right time during hospitalization and gene polymorphisms of adenosine triphosphate binding cassette transporter B1(ABCB1),cytochrome P450(CYP)2C19,CYP3A4,CYP3A5 and nuclear receptor subfamily 1,group I,member 2(NR1I2)were detected.Children who completed 6 months of TAC treatment and follow‑up were included.According to the genotype detection results,children were divided into wild‑type group,heterozy‑gous mutant group,and homozygous mutant group and first dose-adjusted blood trough concentration(C/D)of TAC were compared;they were divided into mutation carrier group(including heterozygous mutation carriers and homozygous mutation carriers)and wild‑type group and the incidence of adverse reactions were com‑pared.Results A total of 39 children were included in the analysis,including 24 males and 15 females,aged 3 to 13 years with a median age of 8 years.The comparison results of the first C/D of TAC among various genotype groups showed that the TAC C/D in children of CYP2C19 homozygous mutant(*2*2)group was higher than that of wild‑type(*1*1)group[3.65(2.78,7.43)μg/L vs.1.53(1.27,3.33)μg/L,P=0.032],TAC C/D in children of CYP3A5 homozygous mutant(*3*3)group was significantly higher than those of the wild‑type(*1*1)group and heterozygous mutation(*1*3)group[3.68(3.05,5.14)μg/L vs.2.10(0.77,3.56)μg/L and 1.74(1.47,3.25)μg/L,P=0.046,P=0.009],and no significant differences were found in TAC C/D among different genotypes in CYP3A4,ABCB1,or NR1I2(all P>0.05).A total of 7 children had adverse re‑actions within 6 months of TAC treatment(Naranjo′s assessment scale,"probable"in 2 children and"possi‑ble"in 5 children),including infection,rash,hypertensive encephalopathy,and convulsions in 4,1,1,1 child,respectively.The incidence of adverse reactions in ABCB1 mutation carrying children(CT and TT)was significantly higher than that in children of wild‑type(CC)group[30.4%(7/23)vs.0(0/16),P=0.033].Conclusion CYP2C19 and CYP3A5 gene polymorphisms have significant effects on TAC blood concentra‑tion,and ABCB1 gene polymorphisms have significant effects on the safety of TAC application,which should be noticed in clinic.
作者 甄淑娟 张建江 曾慧勤 王琴 贾萌萌 Zhen Shujuan;Zhang Jianjiang;Zeng Huiqin;Wang Qin;Jia Mengmeng(Department of Pediatrics,the First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China;Department of Pharmacy,the First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China)
出处 《药物不良反应杂志》 CSCD 2022年第10期515-521,共7页 Adverse Drug Reactions Journal
基金 河南省科技攻关计划项目(SB201901042)。
关键词 肾病综合征 肾病 基因型 儿童 他克莫司 Nephrotic syndrome Nephrosis Genotype Child Tacrolimus
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