The anti-malarial drug halofantrine and its metabolite N-desbutylhalofantrine block HERG potassium channels.
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Mbai M, Rajamani S, January CT
The anti-malarial drug halofantrine and its metabolite N-desbutylhalofantrine block HERG potassium channels.
Cardiovasc Res. 2002 Sep;55(4):799-805.
- PubMed ID
- 12176129 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Halofantrine Potassium voltage-gated channel subfamily H member 2 Protein Humans YesInhibitorDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareHalofantrineLumefantrine Lumefantrine may increase the QTc-prolonging activities of Halofantrine.