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Cardiovascular Research 2002 55(4):799-805; doi:10.1016/S0008-6363(02)00448-0
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

The anti-malarial drug halofantrine and its metabolite N-desbutylhalofantrine block HERG potassium channels

Mackenzi Mbai1, Sridharan Rajamani1 and Craig T January*

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

* Corresponding author. Tel.: +1-608-262-5291; fax: +1-608-263-0405 ctj{at}medicine.wisc.edu

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 (IKr). 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. Conclusion: 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.

KEYWORDS Arrhythmia (mechanisms); Ion channels; Long QT syndrome; Sudden death

1 Authors contributed equally and should be considered co-first authors.


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