Estimating hERG drug binding using temperature-controlled high throughput automated patch clamp

著者: Mette T Christensen, Anders Lindqvist

The human ether-à-go-go related gene (hERG) carries one of the major repolarizing currents in the heart myocytes and block of this channel by certain drugs may lead to prolongation of the cardiac action potential and the potentially lethal arrhythmia torsade de pointes (TdP). Therefore current guidelines are that potency against hERG should be assessed in preclinical drug development. However, not all compounds inhibiting hERG are proarrhythmogenic and more integrated effects of the rug must be taken into consideration.

The comprehensive in vitro proarrhythmic assay (CiPA) initiative have introduced a new paradigm for assessing
proarrhythmic risk based on a thorough understanding of the underlying cellular mechanisms leading to a more predictive estimation of the risk carried by the specific compound.

One pillar of the CiPA paradigm is to measure the major
ionic currents involved in cardiac depolarization and repolarization using the high throughput automated patch clamp (APC) systems. Until recently this has meant that the measurements were carried out at ambient temperature a but recently automated patch clamp instruments with temperature control have become available making it possible to perform up to 384 parallel recordings at controlled temperatures ranging from 10 to 40°C.

Here we estimate potencies and binding kinetics to the hERG channel which are important parameters for the outcome of the risk assessment for a panel of clinical drugs using a Qube APC system equipped with temperature control.