부산대학교 도서관

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 (IC50=0.18 μM) of clomiphene on HERG ionic current (IHERG) recorded from a mammalian cell line expressing HERG channels. Inhibition of IHERG 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 IHERG blockade (p>0.05). Experiments on guinea-pig isolated perfused hearts revealed that, despite its inhibitory action on IHERG, clomiphene produced no significant effect at 1 μM on uncorrected QT interval (p>0.1) nor on rate-corrected QT interval (QTc; p>0.1 for QTc determined using Van de Water’s formula). The disparity between clomiphene’s potent IHERG inhibition and its lack of effect on the QT interval underscores the notion that IHERG pharmacology may best be used alongside other screening methods when investigating the QT-prolonging tendency and related cardiotoxicity of non-cardiac drugs. [Copyright &y& Elsevier]