Electropharmacological assessment of the risk of drug-induced long-QT syndrome using native cardiac cells and cultured cells expressing HERG channels

Abstract

In order to prevent the drug-induced long-QT syndrome it is important to assess the risk in the early phase of drug development. Most of the drugs, which clinically prolong the QT interval and induce torsades de pointes (Tdp), are known to inhibit the rapid component of the delayed rectifier K(+) current (I(Kr)) in cardiac cells. It is acknowledged that HERG (human ether-a-go-go-related gene) encodes the channel pore protein underlying I(Kr). The most sensitive method to evaluate the risk would be electropharmacological assessment using patch clamp techniques. When enzymatically-dissociated native cardiac cells are used, overlapping contamination of the slow component of the delayed rectifier K(+) current (I(Ks)) makes it difficult to analyze the drug effect on I(Kr) accurately. Therefore, heterologous expression systems of HERG channel are usually used to evaluate the inhibitory effect of drugs on I(Kr). Since the Xenopus oocyte system expressing HERG channels appears to be less sensitive to drug inhibition, use of a mammalian cell expression system may be desirable for the screening. A detailed analysis using various pulse protocols may be needed for the careful assessment of the HERG channel inhibition. In addition, many factors that may affect the susceptibility of patients to QT prolongation must be also taken into consideration.