Drug-induced long QT syndrome: hERG K+ channel block and disruption of protein trafficking by fluoxetine and norfluoxetine

Br J Pharmacol. 2006 Nov;149(5):481-9. doi: 10.1038/sj.bjp.0706892. Epub 2006 Sep 11.


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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antidepressive Agents, Second-Generation / adverse effects
  • Antidepressive Agents, Second-Generation / pharmacology
  • Blotting, Western
  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cell Membrane / physiology
  • Cisapride / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Overdose
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • Ether-A-Go-Go Potassium Channels / genetics
  • Ether-A-Go-Go Potassium Channels / metabolism*
  • Female
  • Fluoxetine / adverse effects*
  • Fluoxetine / analogs & derivatives
  • Fluoxetine / pharmacology
  • Humans
  • Long QT Syndrome / chemically induced*
  • Long QT Syndrome / metabolism
  • Long QT Syndrome / physiopathology
  • Membrane Potentials / drug effects
  • Muscle Proteins / antagonists & inhibitors
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Mutation / genetics
  • NAV1.5 Voltage-Gated Sodium Channel
  • Patch-Clamp Techniques
  • Piperidines / pharmacology
  • Protein Transport / drug effects
  • Pyridines / pharmacology
  • Sodium Channels / genetics
  • Sodium Channels / metabolism
  • Time Factors
  • Transfection


  • Antidepressive Agents, Second-Generation
  • Ether-A-Go-Go Potassium Channels
  • Muscle Proteins
  • NAV1.5 Voltage-Gated Sodium Channel
  • Piperidines
  • Pyridines
  • SCN5A protein, human
  • Sodium Channels
  • Fluoxetine
  • E 4031
  • norfluoxetine
  • Cisapride