The anti-malarial drug halofantrine and its metabolite N-desbutylhalofantrine block HERG potassium channels.
OBJECTIVE
The antimalarial drug halofantrine has been associated with QT interval prolongation and with fatal and nonfatal arrhythmias in patients without known underlying cardiac abnormalities. A common target for QT interval-prolonging drugs is the human ether-a-go-go gene (HERG) which encodes the pore forming subunit of the rapidly activating delayed rectifier K(+) current (I(Kr)).


METHODS
We studied the effects of halofantrine (0.1-1000 nM) and its major metabolite N-desbutylhalofantrine (3-1000 nM) on wild type HERG K(+) channels stably expressed in HEK 293 cells, using the whole cell patch-clamp recording technique.


RESULTS
Halofantrine and N-desbutylhalofantrine blocked HERG K(+) channels in a concentration-dependent manner with a half-maximal inhibitory concentration of 21.6 nM (n=31 cells) and 71.7 nM (n=18 cells), respectively. The development of drug block for both halofantrine and N-desbutylhalofantrine required channel activation indicative of open and/or inactivated state block. Drug washout or cell hyperpolarization resulted in minimal current recovery consistent with virtually irreversible binding. Using a ventricular action potential voltage clamp protocol, halofantrine and N-desbutylhalofantrine block of HERG current was greatest during phases 2 and 3 of the action potential waveform.


CONCLUSIONS
We conclude that both halofantrine and N-desbutylhalofantrine cause high affinity block of HERG K(+) channels. Although N-desbutylhalofantrine has been suggested to be a safer antimalarial agent compared to halofantrine, our results suggest that the gain in the safety margin for QT interval prolongation-related cardiotoxicity is minimal.
Mbai
Mackenzi
M
Department of Medicine, Section of Cardiovascular Medicine, Room H6/354 CSC (3248), University of Wisconsin Hospitals and Clinics, 600 Highland Avenue, Madison, WI 53792, USA.
Rajamani
Sridharan
S
January
Craig T
CT
D000200:Action Potentials; D000962:Antimalarials / Q000009:adverse effects* / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D027682:Cation Transport Proteins; D002460:Cell Line; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D020128:Inhibitory Concentration 50; D007668:Kidney; D018408:Patch-Clamp Techniques; D010616:Phenanthrenes / Q000009:adverse effects* / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014162:Transfection
D000962:Antimalarials; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D010616:Phenanthrenes; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C044961:1,3-dichloro-6-trifluoromethyl-9-phenanthryl-3-(n-butyl)aminopropanol; C023768:halofantrine