Inhibition of hERG K+ currents by antimalarial drugs in stably transfected HEK293 cells

Abstract

Several antimalarial drugs are known to produce a QT interval prolongation via a blockade of the rapidly activating delayed rectifier K+ current (IKr), encoded by the human-ether-a-go-go-related gene (hERG). We investigated the influence of lumefantrine and its major metabolite desbutyl-lumefantrine, as well as halofantrine, chloroquine, and mefloquine, on wild type hERG K+ channels in stably transfected human embryonic kidney cells (HEK293) using the whole cell patch-clamp technique. All of the tested antimalarial drugs inhibited the hERG K+ channels in a concentration- and time-dependent manner. Only halofantrine blocked hERG tail currents voltage-dependently. The ranking of the half-maximal inhibitory concentrations (IC50) of the antimalarials was: halofantrine (0.04 microM)<chloroquine (2.5 microM)<mefloquine (2.6 microM)<desbutyl-lumefantrine (5.5 microM)<lumefantrine (8.1 microM). Lumefantrine and desbutyl-lumefantrine showed a slower inhibition of IKr than the other tested antimalarials. In conclusion, lumefantrine and desbutyl-lumefantrine inhibited significantly the hERG tail current with a higher IC50-value than mefloquine, chloroquine and halofantrine. This, together with the calculated cardiac safety indices, suggests that lumefantrine and desbutyl-lumefantrine have a weaker proarrhythmic potential than their comparator compounds.