药学学报, 2019, 54(11): 1895-1902
引用本文:
张国翠, 丰攀峰, 战歌, 吕林, 房利, 李宝馨. 小檗碱类联合用药的心脏安全性评价[J]. 药学学报, 2019, 54(11): 1895-1902.
ZHANG Guo-cui, FENG Pan-feng, ZHAN Ge, L� Lin, FANG Li, LI Bao-xin. Cardiac safety evaluation of berberine combining with berberine-derived medicine[J]. Acta Pharmaceutica Sinica, 2019, 54(11): 1895-1902.

小檗碱类联合用药的心脏安全性评价
张国翠, 丰攀峰, 战歌, 吕林, 房利, 李宝馨
哈尔滨医科大学药学院, 黑龙江 哈尔滨 150081
摘要:
药物诱发心脏毒性是近年备受关注的严重问题,其诱发获得性长QT综合征(long QT syndrome,LQTS)是心脏毒性的重要表现。hERG(human ether-a-go-go-related gene)基因编码快速延迟整流钾通道(rapidly activateddelayed rectifier potassium channel,Ikr)的α亚基,通道在动作电位3期复极过程中起重要作用,当hERG钾通道被药物抑制会导致QT间期延长,伴有尖端扭转型室性心动过速(torsade depointes,Tdp),易致猝死。本文探讨小檗碱类药物与降脂药瑞舒伐他汀及降糖药格列本脲联合应用后对hERG钾通道的影响,评价上述药物联合应用的心脏安全性。利用全细胞膜片钳技术,观察上述药物联合应用后对稳定表达hERG钾通道的HEK293细胞hERG通道的影响。研究显示,小檗碱、二氢小檗碱分别与瑞舒伐他汀联合应用后对hERG电流的抑制作用明显强于单独使用(P<0.05),合用后对hERG通道动力学无影响;小檗碱、二氢小檗碱分别与格列本脲合用后对hERG电流抑制作用明显强于单独使用(P<0.05),合用后与对照组相比均显著缩短通道瞬时失活时间常数(P<0.05),此外,小檗碱与格列本脲合用后抑制通道激活过程(P<0.05);小檗碱与川芎嗪合用后对hERG电流的抑制作用比单用时未见增强。结果表明,小檗碱类药物与瑞舒伐他汀、格列本脲联合应用后对hERG电流的抑制作用明显强于单独使用,小檗碱与川芎嗪合用后对hERG电流的抑制作用与小檗碱单用组相比无显著差异,故当对hERG通道具有抑制作用的两药合用时,诱发QT间期延长的风险会明显增加,心脏安全性降低。
关键词:    小檗碱      二氢小檗碱      瑞舒伐他汀      格列本脲      川芎嗪      hERG     
Cardiac safety evaluation of berberine combining with berberine-derived medicine
ZHANG Guo-cui, FENG Pan-feng, ZHAN Ge, L� Lin, FANG Li, LI Bao-xin
College of Pharmacy, Harbin Medical University, Harbin 150081, China
Abstract:
Drug-induced cardiotoxicity is a serious concern in recent years, and acquired long QT syndrome (LQTS) is an important manifestation of cardiotoxicity. hERG gene encodes the α subunit of the rapidly activated delayed rectifier potassium channel (Ikr), which plays an important role in action potential phase 3 repolarization. Drug inhibition of Ikr/hERG channel leads to prolonged QT interval, accompanied by Tdp malignant arrhythmia, which can cause sudden death. We studied the effect of berberines on the hERG K+ channels after combination with rosuvastatin and glibenclamide, and evaluated the cardiac safety of these drugs in combination. Whole cell patch clamp technique was used to detect the effect of the combinations of these drugs on hERG current on HEK293 cells stably expressing hERG gene. The results showed that the inhibitory effects of berberine or dihydroberberberine combined with rosuvastatin on hERG current were higher than single drug (P<0.05), but the combination had no effect on the kinetics of hERG channel. Berberine or dihydroberberberine combined with glibenclamide had higher inhibitory effects on hERG current than the application of single drug (P<0.05) while the time constant of hERG channel inactivation was shortened after the combination (P<0.05). In addition, the combination of berberine and glibenclamide inhibited hERG channel activation (P<0.05). In conclusion, our results demonstrated that the combination of berberine with rosuvastatin or glibenclamide significantly inhibited hERG current and the inhibition effects were higher than the application alone. Therefore, when the two drugs that have inhibitory effects on the hERG channel are combined, the risk of inducing prolonged QT interval is significantly increased, and therefore reducing cardiac safety.
Key words:    berberine    dihydroberberine    rosuvastatin    glibenclamide    ligustrazine    hERG   
收稿日期: 2019-04-17
DOI: 10.16438/j.0513-4870.2019-0287
基金项目: 国家自然科学基金面上资助项目(81673636).
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