title: 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.
authors.affiliation: Preclinical Safety, Novartis Pharma AG, MUT-2881.205, CH-4002, Basel, Switzerland. Martin.Traebert@pharma.novartis.com
authors.forename: Martin
authors.initials: M
authors.lastname: Traebert
authors.forename: Bérengère
authors.initials: B
authors.lastname: Dumotier
authors.forename: Lothar
authors.initials: L
authors.lastname: Meister
authors.forename: Peter
authors.initials: P
authors.lastname: Hoffmann
authors.forename: Manuel
authors.initials: M
authors.lastname: Dominguez-Estevez
authors.forename: Willi
authors.initials: W
authors.lastname: Suter
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000235:genetics; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D014162:Transfection / Q000379:methods
chemical_list: D000962:Antimalarials; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated