Potent inhibition of human cardiac potassium (HERG) channels by the anti-estrogen agent clomiphene—without QT interval prolongation

Abstract

The acquired form of the long-QT syndrome (LQTS) is a major safety consideration for the development and subsequent use of both cardiac and non-cardiac drugs; it is usually associated with pharmacological inhibition of cardiac HERG-encoded potassium channels. Clomiphene is an anti-estrogen agent used extensively in the treatment of infertility and is not associated with a risk of QT interval prolongation, in contrast to a structurally related compound tamoxifen. We describe here a potent inhibitory effect (IC 50=0.18 μM) of clomiphene on HERG ionic current ( I HERG) recorded from a mammalian cell line expressing HERG channels. Inhibition of I HERG by clomiphene showed voltage-dependence and developed quickly following membrane depolarisation, indicating contingency of block on HERG channel gating. At 100 nM, clomiphene and the related anti-estrogen tamoxifen produced similar levels of I HERG blockade ( p>0.05). Experiments on guinea-pig isolated perfused hearts revealed that, despite its inhibitory action on I HERG, clomiphene produced no significant effect at 1 μM on uncorrected QT interval ( p>0.1) nor on rate-corrected QT interval (QT c; p>0.1 for QT c determined using Van de Water’s formula). The disparity between clomiphene’s potent I HERG inhibition and its lack of effect on the QT interval underscores the notion that I HERG pharmacology may best be used alongside other screening methods when investigating the QT-prolonging tendency and related cardiotoxicity of non-cardiac drugs.