Inhibition of HERG potassium channels by the antimalarial agent halofantrine

1 Halofantrine is a widely used antimalarial agent which has been associate d with prolongation of the 'QT interval' of the electrocardiogram (ECG), to rsades de pointes and sudden death. Whilst QT prolongation is consistent wi th halofantrine-induced increases in cardiac ventricular action potential d uration, the cellular mechanism for these observations has not been previou sly reported. 2 The delayed rectifier potassium channel, I-Kr, is a primary site of actio n of drugs causing QT prolongation and is encoded by the human-ether-a-go-g o-related gene (HERG). We examined the effects of halofantrine on HERG pota ssium channels stably expressed in Chinese hamster ovary (CHO-K1) cells. 3 Halofantrine blocked HERG tail currents elicited on repolarization to -60 mV from +30 mV with an IC50 of 196.9 nM. The therapeutic plasma concentrat ion range for halofantrine is 1.67-2.98 mu M. 4 Channel inhibition by halofantrine exhibited time-, voltage- and use-depe ndence. Halofantrine did not alter the time course of channel activation or deactivation, but inactivation was accelerated and there was a 20 mV hyper polarizing shift in the mid-activation potential of steady-state inactivati on. Block was enhanced by pulses that render channels inactivated, and chan nel blockade increased with increasing duration of depolarizing pulses. 5 We conclude that HERG channel inhibition by halofantrine is the likely un derlying cellular mechanism for QT prolongation. Our data suggest preferent ial binding of halofantrine to the open and inactivated channel states.