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The anti-malarial drug halofantrine and its metabolite N-desbutylhalofantrine block HERG potassium channels.
Cardiovasc Res. 2002 Sep; 55(4):799-805.CR

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+Show Affiliations

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.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12176129

Citation

Mbai, Mackenzi, et al. "The Anti-malarial Drug Halofantrine and Its Metabolite N-desbutylhalofantrine Block HERG Potassium Channels." Cardiovascular Research, vol. 55, no. 4, 2002, pp. 799-805.
Mbai M, Rajamani S, January CT. The anti-malarial drug halofantrine and its metabolite N-desbutylhalofantrine block HERG potassium channels. Cardiovasc Res. 2002;55(4):799-805.
Mbai, M., Rajamani, S., & January, C. T. (2002). The anti-malarial drug halofantrine and its metabolite N-desbutylhalofantrine block HERG potassium channels. Cardiovascular Research, 55(4), 799-805.
Mbai M, Rajamani S, January CT. The Anti-malarial Drug Halofantrine and Its Metabolite N-desbutylhalofantrine Block HERG Potassium Channels. Cardiovasc Res. 2002;55(4):799-805. PubMed PMID: 12176129.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The anti-malarial drug halofantrine and its metabolite N-desbutylhalofantrine block HERG potassium channels. AU - Mbai,Mackenzi, AU - Rajamani,Sridharan, AU - January,Craig T, PY - 2002/8/15/pubmed PY - 2002/10/31/medline PY - 2002/8/15/entrez SP - 799 EP - 805 JF - Cardiovascular research JO - Cardiovasc. Res. VL - 55 IS - 4 N2 - 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. SN - 0008-6363 UR - https://www.unboundmedicine.com/medline/citation/12176129/The_anti_malarial_drug_halofantrine_and_its_metabolite_N_desbutylhalofantrine_block_HERG_potassium_channels_ L2 - https://academic.oup.com/cardiovascres/article-lookup/doi/10.1016/s0008-6363(02)00448-0 DB - PRIME DP - Unbound Medicine ER -