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Blockade of HERG and Kv1.5 by ketoconazole.
J Pharmacol Exp Ther. 1998 Aug; 286(2):727-35.JP

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 Xenopus oocytes and compared their sensitivities to ketoconazole. HERG and Kv1.5 currents were reduced comparably with apparent IC50 values of 49 microM and 107 microM, 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.

Authors+Show Affiliations

Rammelkamp Center for Research, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, 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

9694927

Citation

Dumaine, R, et al. "Blockade of HERG and Kv1.5 By Ketoconazole." The Journal of Pharmacology and Experimental Therapeutics, vol. 286, no. 2, 1998, pp. 727-35.
Dumaine R, Roy ML, Brown AM. Blockade of HERG and Kv1.5 by ketoconazole. J Pharmacol Exp Ther. 1998;286(2):727-35.
Dumaine, R., Roy, M. L., & Brown, A. M. (1998). Blockade of HERG and Kv1.5 by ketoconazole. The Journal of Pharmacology and Experimental Therapeutics, 286(2), 727-35.
Dumaine R, Roy ML, Brown AM. Blockade of HERG and Kv1.5 By Ketoconazole. J Pharmacol Exp Ther. 1998;286(2):727-35. PubMed PMID: 9694927.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Blockade of HERG and Kv1.5 by ketoconazole. AU - Dumaine,R, AU - Roy,M L, AU - Brown,A M, PY - 1998/8/8/pubmed PY - 1998/8/8/medline PY - 1998/8/8/entrez SP - 727 EP - 35 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 286 IS - 2 N2 - 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 Xenopus oocytes and compared their sensitivities to ketoconazole. HERG and Kv1.5 currents were reduced comparably with apparent IC50 values of 49 microM and 107 microM, 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/9694927/Blockade_of_HERG_and_Kv1_5_by_ketoconazole_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9694927 DB - PRIME DP - Unbound Medicine ER -