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

Abstract

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.

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.

• Authors: Mackenzi Mbai, Sridharan Rajamani, Craig T January
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 55 Issue 4 Pg. 799-805 (Sep 2002) ISSN: 0008-6363 [Print] England
• PMID: 12176129 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antimalarials
• Cation Transport Proteins
• DNA-Binding Proteins
• ERG protein, human
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels
• KCNH2 protein, human
• KCNH6 protein, human
• Phenanthrenes
• Potassium Channels
• Potassium Channels, Voltage-Gated
• Trans-Activators
• Transcriptional Regulator ERG
• 1,3-dichloro-6-trifluoromethyl-9-phenanthryl-3-(n-butyl)aminopropanol
• halofantrine

Topics

• Action Potentials
• Antimalarials (adverse effects, pharmacology)
• Arrhythmias, Cardiac (chemically induced)
• Cation Transport Proteins
• Cell Line
• DNA-Binding Proteins
• Dose-Response Relationship, Drug
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels
• Humans
• Inhibitory Concentration 50
• Kidney
• Patch-Clamp Techniques
• Phenanthrenes (adverse effects, pharmacology)
• Potassium Channels (drug effects, genetics)
• Potassium Channels, Voltage-Gated
• Trans-Activators
• Transcriptional Regulator ERG
• Transfection