BACKGROUND AND PURPOSE: Fluoxetine (Prozac) is a widely prescribed drug in 
adults and children, and it has an active metabolite, norfluoxetine, with a 
prolonged elimination time. Although uncommon, Prozac causes QT interval 
prolongation and arrhythmias; a patient who took an overdose of Prozac exhibited 
a prolonged QT interval (QTc 625 msec). We looked for possible mechanisms 
underlying this clinical finding by analysing the effects of fluoxetine and 
norfluoxetine on ion channels in vitro.
EXPERIMENTAL APPROACH: We studied the effects of fluoxetine and norfluoxetine on 
the electrophysiology and cellular trafficking of hERG K+ and SCN5A Na+ channels 
heterologously expressed in HEK293 cells.
KEY RESULTS: Voltage clamp analyses employing square pulse or ventricular action 
potential waveform protocols showed that fluoxetine and norfluoxetine caused 
direct, concentration-dependent, block of hERG current (IhERG). Biochemical 
studies showed that both compounds also caused concentration-dependent 
reductions in the trafficking of hERG channel protein into the cell surface 
membrane. Fluoxetine had no effect on SCN5A channel or HEK293 cell endogenous 
current. Mutations in the hERG channel drug binding domain reduced fluoxetine 
block of IhERG but did not alter fluoxetine's effect on hERG channel protein 
trafficking.
CONCLUSIONS AND IMPLICATIONS: Our findings show that both fluoxetine and 
norfluoxetine at similar concentrations selectively reduce IhERG by two 
mechanisms, (1) direct channel block, and (2) indirectly by disrupting channel 
protein trafficking. These two effects are not mediated by a single drug binding 
site. Our findings add complexity to understanding the mechanisms that cause 
drug-induced long QT syndrome.