文章摘要
孙红云,邢红艳,赵 琪,王淑颜,宋 征,李 华,汪溪洁.9种不同心血管风险的临床药物对hERG钾通道的作用[J].南京医科大学学报,2019,(1):1~9
9种不同心血管风险的临床药物对hERG钾通道的作用
Effects of nine clinical drugs with different careiovascular risk on hERG potassium channels
投稿时间:2018-03-14  
DOI:10.7655/NYDXBNS20190101
中文关键词: 药物验证  尖端扭转型室速  hERG钾通道  全细胞膜片钳
英文关键词: drugs evaluation  torsade de pointes  hERG  whole⁃cell patch clamp
基金项目:国家“重大新药创制”科技重大专项(2015ZX09501004?002?006);上海市科委“科技创新行动计划”项目(17140900700)
作者单位
孙红云 中国医药工业研究总院国家上海新药安全评价研究中心上海 201203上海益诺思生物技术股份有限公司上海 201203 
邢红艳 中国医药工业研究总院国家上海新药安全评价研究中心上海 201203上海益诺思生物技术股份有限公司上海 201203 
赵 琪 中国医药工业研究总院国家上海新药安全评价研究中心上海 201203上海益诺思生物技术股份有限公司上海 201203 
王淑颜 中国医药工业研究总院国家上海新药安全评价研究中心上海 201203上海益诺思生物技术股份有限公司上海 201203 
宋 征 中国医药工业研究总院国家上海新药安全评价研究中心上海 201203上海益诺思生物技术股份有限公司上海 201203 
李 华 中国医药工业研究总院国家上海新药安全评价研究中心上海 201203上海益诺思生物技术股份有限公司上海 201203 
汪溪洁 中国医药工业研究总院国家上海新药安全评价研究中心上海 201203上海益诺思生物技术股份有限公司上海 201203 
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中文摘要:
      目的:在GLP实验室评估膜片钳检测临床用药物对hERG(human ether?à?go?go related gene)钾通道作用的差异性和重复性,研究9种致尖端扭转型室速(TdP)风险的临床用药物(高风险临床用药物:苄普地尔、奎尼丁、索他洛尔;中风险临床用药物:昂丹司琼、西沙比利、特非那定;低风险临床用药物:雷诺嗪、维拉帕米和美西律)对hERG钾通道的阻断作用。方法:采用全细胞膜片钳技术记录不同浓度的苄普地尔、奎尼丁、索他洛尔、昂丹司琼、西沙比利、特非那定、雷诺嗪、维拉帕米和美西律作用于外源稳定转染表达hERG钾通道的HEK293细胞(hERG?HEK293稳态细胞)后hERG电流(IKr)的变化,研究上述临床用药物对IKr作用的浓度依赖性及半数抑制浓度(IC50)。结果:9种临床用药物对hERG?HEK293细胞上IKr作用具有浓度依赖性,且高风险临床用药物苄普地尔和奎尼丁的IC50值分别为98.32 nmol/L和1.95 μmol/L,索他洛尔的IC50值大于300 μmol/L;中风险临床用药物昂丹司琼、西沙比利和特非那定的IC50值分别为0.94 μmol/L、39.10 nmol/L和128.58 nmol/L;低风险临床用药物雷诺嗪、维拉帕米和美西律的IC50值分别为9.94 μmol/L、235.49 nmol/L和65.56 μmol/L。本实验所得临床用药物IC50值基本与文献相符。结论:临床用药物致TdP风险与hERG通道的阻滞作用密切相关,但hERG通道阻断不等同于TdP风险,还与心脏上表达的多种离子通道有关,某些临床用药物可以通过阻断钠通道和钙通道而降低风险。本研究结果提示本方法所得数据可靠,为国内GLP实验室进行hERG钾通道评价研究提供了参考依据,可用于药物心脏毒性评价。
英文摘要:
      Objective:To assess the variability and reproducibility of patch clamp platforms/sites for defining clinical drug effects on human ether?à?go?go related gene(hERG) currents across and between platforms and sites and to investigate the blocking effect of nine clinical drugs that have high(bepridil,quinidine,sotalol),intermediate(ondansetron,cisapride,terfenadine)and low(ranolazine,verapamil and mexiletine)torsade de pointes risk(TdP)on hERG potassium channel. Methods:The whole?cell patch clamp technique was used to record the change in hERG potassium current(IKr)on HEK293 cells that stably expressed hERG potassium channel(hERG?HEK293 steady?state cells),which was treated with four test concentrations of bepridil,quinidine,sotalol,ondansetron,cisapride,terfenadine,ranolazine,verapamil and mexiletine,to study the concentration?dependence of the effects on IKr and the half maximal inhibitory concentration(IC50). Resuts:All of the nine clinical drugs tested produced a concentration?dependent reduction of hERG current. The IC50 values of bepridil and quinidine(high TdP risk clinical drugs) were about 98.32 nmol/L and 1.95 μmol/L,respectively,and the IC50 values of sotalol was >300 μmol/L. The IC50 values of ondansetron,cisapride,terfenadine(intermediate TdP risk clinical drugs)were 0.94 μmol/L,39.10 nmol/L,128.58 nmol/L,respectively. The IC50 values of ranolazine,verapamil and mexiletine(low TdP risk clinical drugs)were 9.94 μmol/L,235.49 nmol/L and 65.56 μmol/L,respectively. The IC50 values for the nine clinical drugs corresponded well to those published within the literature. Conclusion:The risk of drug?induced TdP is closely related to the block of the hERG channel,but the hERG channel block is lack of specificity as a predictor of TdP,which is also associated with multiple ion channel effects. Some clinical drugs also block Nav1.5?late and/or Cav1.2 currents,which can reduce the risk of TdP caused by hERG block. The data obtained by this method is reliable,which provides a reference for the hERG block test performed by domestic GLP laboratories and can be used for the safety evaluation of drug cardiac toxicity.
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