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Vol. 286, Issue 2, 727-735, August 1998
Rammelkamp Center for Research, MetroHealth Medical Center, Case
Western Reserve University School of Medicine, Cleveland Ohio
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 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.
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