Blockade of HERG and Kv1.5 by Ketoconazole1

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 pre-viously showed that terfenadine blocked HERG (Human Ether-a-Gogo Related Gene), an important component of the repo-larizing 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 potas-sium current), an important component of human atrial ultra-rapid delayed rectifier current. Whether Kv1.5 and HERG pro-teins are direct targets for ketoconazole has yet to be addressed. We heterologously expressed HERG and Kv1.5 i