Fluoxetine and its metabolite norfluoxetine inhibit the slow delayed rectifier potassium current (IKs), contributing to drug-induced long QT syndrome, especially in KCNQ1 mutation carriers.
Do fluoxetine and norfluoxetine block IKs and contribute to drug-induced long QT syndrome, particularly in K422T mutation carriers?
IKs blockade by drugs such as fluoxetine/norfluoxetine contributes importantly to drug-induced long QT syndrome, highlighting the need for IKs screening in drug safety tests.
BACKGROUND: Drug-induced long QT syndrome is generally ascribed to inhibition of the cardiac rapid delayed rectifier potassium current (IKr). Effects on the slow delayed rectifier potassium current (IKs) are less recognized. Triggered by a patient who carried the K422T mutation in KCNQ1 (encoding the α-subunit of the IKs channel), who presented with excessive QT prolongation and high serum levels of norfluoxetine, we investigated the effects of fluoxetine and its metabolite norfluoxetine on IKs. METHODS AND RESULTS: ECG data from mutation carriers and noncarriers revealed that the K422T mutation per se had mild clinical effects. Patch clamp studies, performed on HEK293 cells, showed that heterozygously expressed K422T KCNQ1/KCNE1 channels had a positive shift in voltage dependence of activation and an increase in deactivation rate. Fluoxetine and its metabolite norfluoxetine both inhibited KCNQ1/KCNE1 current, with norfluoxetine being the most potent. Moreover, norfluoxetine increased activation and deactivation rates. Computer simulations of the effects of norfluoxetine on IKs and IKr demonstrated significant action potential prolongation, to which IKs block contributed importantly. Although the effects of the mutation per se were small, additional IKs blockade by norfluoxetine resulted in more prominent QTc prolongation in mutation carriers than in noncarriers, demonstrating synergistic effects of innate and drug-induced IKs blockade on QTc prolongation. CONCLUSIONS: IKs blockade contributes importantly to drug-induced long QT syndrome, especially when repolarization reserve is reduced. Drug safety tests might have to include screening for IKs blockade.
Veerman et al. (Sun,) conducted a other in Drug-induced long QT syndrome. Fluoxetine and norfluoxetine was evaluated on IKs blockade and QTc prolongation. Fluoxetine and its metabolite norfluoxetine inhibit the slow delayed rectifier potassium current (IKs), contributing to drug-induced long QT syndrome, especially in KCNQ1 mutation carriers.