HERG electrophysiology

Compound In vitro hepatic hERG radioligand hERG electrophysiology... 

N., Strandlund, G., Boyer, S. (2007) Development, interpretation and temporal evaluation of a global QSAR of hERG electrophysiology screening data. / Comput Aided Mol Des 21, 189-206. 

Several studies support the notion that the basic mechanism by which many drugs prolong the QT interval is related to blockade of potassium currents. For instance, several antihistamines, antibacterial macrolides, fluoroquinolones and antipsychotics were shown to inhibit the rapid component of the delayed rectifier K+ current (fKr) in electrophysiological studies and to block potassium channels encoded by hERG [37-42]. 

In conclusion, QT prolongation by hERG channel blockers is per se dose dependent, whereas actual occurrence of TdP depends on the repolarization reserve, which is variable among subjects and over time. The exception to the mle are those hERG blockers with multiple, sometimes complementary electrophysiological actions, which lead to a bell-shaped concentration-response curve [109]. 

A recent study determined the myocardium to plasma concentration ratios of five antipsychotics and underscored the importance of interpreting hERG channel and electrophysiological data in conjunction with other pharmacokinetic parameters [114]. 

Zhou, Z., Vorperian, V.R., Gong, Q., Zhang, S. and January, C.T. (1999) Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole. Journal of Cardiovascular Electrophysiology, 10, 836-843. 

The potential of drugs to cause QT prolongation and the associated risk of cardio-toxicity remains an important issue in drug development. Although the advent of automated electrophysiological systems and other predinical screens has helped in early identification of hERG channel blockers, the outcome can be highly unsatisfactory. The process is wasteful and expensive and the development of potentially valuable compounds is halted. The wealth of information continually uncovered... 

Automated tight seal electrophysiology for assessing the potential hERG liability of pharmaceutical compounds. ASSAY and Drug Development Technologies, 2, 497-506. 

Bridgland-Taylor, M.H. et al. 2006. Optimization and validation of a medium-throughput electrophysiology-based hERG assay using IonWorks HT. J. Pharmacol. Toxicol. Meth. 54, 189-199. 

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