Importance of modelling hERG binding in predicting drug-induced action potential prolongations for drug safety assessment.

ABSTRACT: Reduction of the rapid delayed rectifier potassium current (I _Kr) via drug binding to the human Ether-à-go-go-Related Gene (hERG) channel is a well recognised mechanism that can contribute to an increased risk of Torsades de Pointes. Mathematical models have been created to replicate the effects of channel blockers, such as reducing the ionic conductance of the channel. Here, we study the impact of including state-dependent drug binding in a mathematical model of hERG when translating hERG inhibition to action potential changes. We show that the difference in action potential predictions when modelling drug binding of hERG using a state-dependent model versus a conductance scaling model depends not only on the properties of the drug and whether the experiment achie

SUBMITTER: Farm HJ 

PROVIDER: S-EPMC10067903 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature