Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 484, Issue 1, Pages 41-48Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2003.11.003
Keywords
hERG K+ channel; electrophysiology; antimalarial drug; IC50
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Several antimalarial drugs are known to produce a QT interval prolongation via a blockade of the rapidly activating delayed rectifier K+ current (I-Kr), 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 muM) < chloroquine (2.5 muM) < mefloquine (2.6 muM) < desbutyl-lumefantrine (5.5 muM) < lumefantrine (8.1 muM). 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. (C) 2003 Elsevier B.V. All rights reserved.
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