Rampe David, Brown Arthur M
Disposition, Safety, and Animal Research, Sanofi, Inc., Route 202-206, Bridgewater, NJ 08807, USA.
J Pharmacol Toxicol Methods. 2013 Jul-Aug;68(1):13-22. doi: 10.1016/j.vascn.2013.03.005. Epub 2013 Mar 26.
The human ether-a-go-go-related gene (hERG, Kv11.1) K(+) channel plays an important role in cardiac repolarization. Following its cloning and expression it was established that inhibition of this channel was the molecular mechanism for many non-antiarrhythmic drugs that produce torsades de pointes associated with QT prolongation. Therefore the study of in vitro drug-hERG interactions has become an important part of modern safety pharmacology. Manual and automated patch clamp electrophysiology, in silico modeling, and hERG trafficking assays have been developed to aid in this study. The correlation between in vitro hERG IC50, drug exposure, QT prolongation in the thorough QT clinical trial and risk of TdP has greatly reduced drug withdrawals due to TdP. However a significant association with Type 1 errors in particular remains and may have a negative impact on drug development. Combining hERG data with other non-clinical and clinical markers of proarrhythmia will increase the specificity and sensitivity of cardiac risk assessment. hERG will continue to play an important role in drug development and safety pharmacology in the future.
人类醚-去极化相关基因（hERG，Kv11.1）钾通道在心脏复极化过程中发挥重要作用。该通道被克隆并表达后，人们确定许多导致尖端扭转型室速伴QT间期延长的非抗心律失常药物的分子机制是对该通道的抑制作用。因此，体外药物与hERG相互作用的研究已成为现代安全药理学的重要组成部分。手动和自动膜片钳电生理学、计算机模拟以及hERG转运测定法已被开发出来以辅助此项研究。体外hERG半数抑制浓度（IC50）、药物暴露、全面QT临床试验中的QT间期延长与尖端扭转型室速风险之间的相关性已大大减少了因尖端扭转型室速导致的药物撤市情况。然而，尤其是与一类错误仍存在显著关联，这可能会对药物研发产生负面影响。将hERG数据与其他心律失常的非临床和临床标志物相结合，将提高心脏风险评估的特异性和敏感性。未来，hERG将继续在药物研发和安全药理学中发挥重要作用。
