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Utility of hERG Assays as Surrogate Markers of Delayed Cardiac Repolarization and QT SafetyDeptartment of Integrative Pharmacology, Abbott Laboratories, Abbott Park, Illinois 60064-6119, USA Correspondence: Address correspondence to: Gary Gintant, Dept. of Integrative Pharmacology (R46R, Bldg AP-9), Abbott Laboratories, 100 Abbott Park Rd., Abbott Park, IL 60064-6119, USA; e-mail:Gary.Gintant{at}abbott.com HERG (human-ether-a-go-go-related gene) encodes for a cardiac potassium channel that plays a critical role in defining ventricular repolarization. Noncardiovascular drugs associated with a rare but potentially lethal ventricular arrhythmia (Torsades de Pointes) have been linked to delayed cardiac repolarization and block of hERG current. This brief overview will discuss the role of hERG current in cardiac electrophysiology, its involvement in drug-induced delayed repolarization, and approaches used to define drug effects on hERG current. In addition, examples of hERG blocking drugs acting differently (i.e., overt and covert hERG blockade due to multichannel block) together with the utility and limitations of hERG assays as tools to predict the risk of delayed repolarization and proarrhythmia are discussed.
Key Words: HERG • QT interval • Torsades de Pointes • arrhythmias • APD • repolarization Abbreviations: APD, action potential duration • CHO, Chinese hamster ovary • EADs, early afterdepolarizations • ECG, electrocardiogram • HERG, human ether-a-go-go-related gene • HEK, human embryonic kidney • msec, milliseconds • QRS, QRS interval on the ECG • QT, QT interval on the ECG • TdP, Torsades de Pointes
Toxicologic Pathology, Vol. 34, No. 1,
81-90 (2006) |
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