生理药动学模型结合全细胞膜片钳技术评价胺碘酮和去乙基胺碘酮的体外心脏安全性  

Cardiac safety assessment of amiodarone and desethylamiodarone in vitro evaluated by physiologically based pharmacokinetic model and whole cell patch clamp technique

作　　者：杜海燕[1] 李静[1] 张颖超[1] 赵桂平[1] 刘之光 郭成军[2] 苏俊武[3] 林阳[1] Du Haiyan;Li Jing;Zhang Yingchao;Zhao Guiping;Liu Zhiguang;Guo Chengjun;Su Junwu;Lin Yang(Department of Pharmacy,Beijing Anzhen Hospital,Capital Medical University,Beijing 100029,China;Department of Cardiology,Beijing Anzhen Hospital,Capital Medical Universityy Beijing 100029,China;Pediatric of Cardiac Center,Beijing Anzhen Hospital,Capital Medical University,Beijing 100029,China)

机构地区：[1]首都医科大学附属北京安贞医院药事部,北京100029 [2]首都医科大学附属北京安贞医院心内科,北京100029 [3]首都医科大学附属北京安贞医院小儿心脏中心,北京100029

出　　处：《中国医药》2022年第7期1061-1064,共4页China Medicine

基　　金：国家“重大新药创制”科技重大专项(2017ZX09304017)。

摘　　要：目的通过生理药动学(PBPK)模型结合全细胞膜片钳技术研究胺碘酮及其活性代谢产物去乙基胺碘酮对心肌细胞hERG通道和动作电位的影响,评价其体外心脏安全性。方法基于复合PBPK模型预测胺碘酮、去乙基胺碘酮在人体心肌药动学曲线。选用模型预测的胺碘酮、去乙基胺碘酮浓度(预测胺碘酮血浆浓度0.76 mg/L,心肌浓度17 mg/L)、(预测去乙基胺碘酮血浆浓度0.13 mg/L,心肌浓度8.5、17 mg/L)分别灌流HEK293细胞(hERG)、人干细胞诱导分化心肌细胞,采用全细胞膜片钳技术记录并观察药物对外向钾流、心肌细胞动作电位的影响。结果PBPK模型预测胺碘酮心肌浓度约为血浆浓度的23倍,而去乙基胺碘酮心肌浓度是血浆的约130倍。静脉滴注或口服多次给药后胺碘酮的血浆、心肌浓度均基本保持恒定,而去乙基胺碘酮的血浆、心肌浓度均呈持续升高,消除缓慢,易蓄积。胺碘酮和去乙基胺碘酮均对hERG通道有较强的抑制作用,并呈浓度依赖性;胺碘酮在血浆浓度、心肌浓度下,对hERG通道的抑制率分别为78.9%和95.8%,去乙基胺碘酮在血浆浓度、心肌浓度下(0.13、8.5、17 mg/L)对hERG通道的抑制率分别为28.3%、87.4%和96.7%。胺碘酮、去乙基胺碘酮在血浆浓度下对心肌细胞动作电位的影响不显著,但在心肌浓度下对动作电位幅度、动作电位时程、静息电位均有较强的抑制作用,并使动作电位发放频率加快,且呈现浓度依赖性。结论临床常用剂量下,分布在心肌的胺碘酮、去乙基胺碘酮对钾离子流、心肌动作电位均有明显的抑制作用。这种抑制作用可能对心律失常的心肌在一定程度上有益,但可能具有一定的安全性风险,特别是去乙基胺碘酮在心肌组织的蓄积效应。Objective To study the effects of amiodarone and desethylamiodarone on hERG channel and action potential of myocardium,based on physiologically based pharmacokinetic(PBPK)model and whole cell patch clamp technique,and to evaluate its cardiac safety in vitro.Methods Pharmacokinetic curves of amiodarone and desethylamiodarone in human myocardium were predicted based on composite PBPK model.Doses of amiodarone(predicted plasma concentration 0.76 mg/L,myocardial concentration 17 mg/L)and desethylamiodarone(predicted plasma concentration 0.13 mg/L,myocardial concentration 8.5 and 17 mg/L)which were predicted by the model were infused with HEK293 cells(hERG)and human induced pluripotent stem cell-derived cardiomyocytes.The whole cell patch clamp technique was used to record the effect of drugs on outward potassium current and action potential of myocardium.Results The PBPK model predicted that the amiodarone concentration in myocardium was up to 23 times higher than the plasma concentration,and the myocardial/plasma concentration ratio of desethylamiodarone was about 130 times higher.The amiodarone concentrations in plasma or myocardium were basically constant after multiple intravenous or oral administration,while the desethylamiodarone concentrations in plasma and myocardial were continuously increased,with slow elimination and accumulation.Both amiodarone and desethylamiodarone had strong inhibitory effect on hERG channel with concentrate-dependent.The inhibitory rates of amiodarone on hERG channel at plasma and myocardial concentration were 78.9% and 95.8% respectively.The inhibitory rates of deethylamiodarone on hERG channel at plasma concentration and myocardial concentration(0.13,8.5 and 17 mg/L)were 28.3%,87.4% and 96.7% respectively.Amiodarone and deethylamiodarone had no significant effect on the action potential of myocardium at plasma concentration,but they had strong inhibitory effects on the amplitude and duration of action potential and resting potential at myocardial concentration,which accelerated the

关 键 词：生理药动学模型 全细胞膜片钳 胺碘酮 去乙基胺碘酮 心脏安全性 

分 类 号：R97[医药卫生—药品]