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Research ArticleArticle

Blockade of HERG and Kv1.5 by Ketoconazole

Robert Dumaine, Mary-Louise Roy and Arthur M. Brown
Journal of Pharmacology and Experimental Therapeutics August 1998, 286 (2) 727-735;
Robert Dumaine
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Mary-Louise Roy
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Arthur M. Brown
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Abstract

Ketoconazole, a widely used fungicide in patients, has been associated with Q-T prolongation and torsade de pointes when co-administered with terfenadine (Seldane). Both compounds use the same cytochrome-P450 metabolic pathway, resulting in an increase in plasma concentration of terfenadine. We previously showed that terfenadine blocked HERG (Human Ether-a-Gogo Related Gene), an important component of the repolarizing cardiac delayed rectifier IK with concentration needed to obtain 50% of the block (IC50) in the therapeutic range (300 nM). Another target is Kv1.5 (delayed outward rectifier potassium current), an important component of human atrial ultrarapid delayed rectifier current. Whether Kv1.5 and HERG proteins are direct targets for ketoconazole has yet to be addressed. We heterologously expressed HERG and Kv1.5 in Xenopusoocytes and compared their sensitivities to ketoconazole. HERG and Kv1.5 currents were reduced comparably with apparent IC50values of 49 μM and 107 μM, respectively, when measured using the two-microelectrode recording technique. The differences in the IC50 may help explain the preferential ventricular origin of the ketoconazole-associated arrhythmias during overdose. The mechanism of block was different between Kv1.5 and HERG. Cumulative application of terfenadine and ketoconazole at their respective IC50 concentrations resulted in current reductions that suggest an additive rather than a competitive type of block by the two drugs. We conclude that ketoconazole may potentiate the effects of terfenadine first by an indirect pharmacokinetic action to elevate plasma levels and second by a direct pharmacodynamic action on HERG currents. These potential dual actions on HERG currents suggest that precautions should be taken in long-term ketoconazole treatment, particularly for patients who have decreased liver function or are on a drug regimen requiring simultaneous medications that use cytochrome-P450 for breakdown, such as terfenadine or erythromycin, or Class III antiarrhythmic drugs.

Footnotes

  • Send reprint requests to: Robert Dumaine Ph.D., Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, NY 13501.

  • ↵1 Dr. Dumaine was supported by postdoctoral fellowships from the Heart and Stroke Foundation of Canada and Le Fonds de la Recherche en Santé du Québec. Dr. Roy was supported by a grant from the American Heart Association (Northeast Ohio Affiliate). This work was supported by NIH grants NS 23877, HL 36930 and HL 55404 to Dr. A. M. Brown.

  • This work was supported by Grants MS 23877-13, HL 36930-13 and HL 55404-02 to A.M.B.

  • Abbreviations:
    IK
    cardiac delayed rectifier current
    IKr
    rapid component of IK
    IKs
    slow component of IK
    IKur
    ultrarapid delayed rectifier current (atrium)
    Ito
    transient outward current
    IC50
    concentration needed to obtain 50% of the block
    DMSO
    dimethyl sulfoxide
    I-V
    current-voltage
    AP
    action potential
    HERG
    Human Ether-a-GoGo Related Gene
    CYP3A4-P450
    cytochrome P450
    • Received December 15, 1997.
    • Accepted April 28, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 286, Issue 2
1 Aug 1998
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Research ArticleArticle

Blockade of HERG and Kv1.5 by Ketoconazole

Robert Dumaine, Mary-Louise Roy and Arthur M. Brown
Journal of Pharmacology and Experimental Therapeutics August 1, 1998, 286 (2) 727-735;

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Research ArticleArticle

Blockade of HERG and Kv1.5 by Ketoconazole

Robert Dumaine, Mary-Louise Roy and Arthur M. Brown
Journal of Pharmacology and Experimental Therapeutics August 1, 1998, 286 (2) 727-735;
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