Acquired QT interval prolongation and HERG: implications for drug discovery and development.
Putative interactions between the Human Ether-a-go-go Related Gene (HERG), QT interval prolongation and Torsades de Pointes (TdP) are now integral components of any discussion on drug safety. HERG encodes for the inwardly rectifying potassium channel (I(Kr)), which is essential to the maintenance of normal cardiac function. HERG channel mutations are responsible for one form of familial long QT syndrome, a potentially deadly inherited cardiac disorder associated with TdP. Moreover, drug-induced (acquired) QT interval prolongation has been associated with an increase in the incidence of sudden unexplained deaths, with HERG inhibition implicated as the underlying cause. Subsequently, a number of non-cardiovascular drugs which induce QT interval prolongation and/or TdP have been withdrawn. However, a definitive link between HERG, QT interval prolongation and arrhythmogenesis has not been established. Nevertheless, this area is subject to ever increasing regulatory scrutiny. Here we review the relationship between HERG, long QT syndrome and TdP, together with a summary of the associated regulatory issues, and developments in pre-clinical screening.
Finlayson
Keith
K
Fujisawa Institute of Neuroscience in Edinburgh, University of Edinburgh, 1 George Square, Edinburgh EH8 9JZ, UK. Keith.Finlayson@ed.ac.uk
Witchel
Harry J
HJ
McCulloch
James
J
Sharkey
John
J
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002986:Clinical Trials as Topic; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006321:Heart / Q000502:physiology; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D016171:Torsades de Pointes / Q000139:chemically induced
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D024642:Potassium Channels, Voltage-Gated