Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers

Clin Pharmacol Ther. 2003 Mar;73(3):170-7. doi: 10.1067/mcp.2003.28.


Background and objectives: Duloxetine, a potent dual reuptake inhibitor of serotonin and norepinephrine currently undergoing clinical investigation for treatment of depression and stress urinary incontinence, has the potential to act as both a substrate and an inhibitor of cytochrome P4502D6 (CYP2D6). Our objectives were to determine the effect of duloxetine on the pharmacokinetics of desipramine, a tricyclic antidepressant metabolized by CYP2D6 (study 1), and the effect of paroxetine, a potent CYP2D6 inhibitor, on duloxetine pharmacokinetics (study 2).

Methods: Subjects were healthy men and women between 21 and 63 years old. All subjects were genotypically CYP2D6 extensive metabolizers. In study 1, 50 mg of desipramine was administered as a single dose alone and in the presence of steady-state duloxetine 60 mg twice daily. In study 2, steady-state pharmacokinetics of duloxetine 40 mg once daily were determined in the presence and absence of steady-state paroxetine 20 mg once daily.

Results: Duloxetine increased the maximum plasma concentration of desipramine 1.7-fold and the area under the concentration-time curve 2.9-fold. Paroxetine increased the maximum plasma concentration of duloxetine and the area under the concentration-time curve at steady state 1.6-fold. Reports of adverse events were similar whether duloxetine was administered alone or in combination with desipramine or paroxetine.

Conclusion: Duloxetine 60 mg twice daily is a moderately potent CYP2D6 inhibitor, intermediate between paroxetine and sertraline. The potent CYP2D6 inhibitor paroxetine has a moderate effect on duloxetine concentrations. The results of these 2 studies suggest that caution should be used when CYP2D6 substrates and inhibitors are coadministered with duloxetine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antidepressive Agents, Tricyclic / administration & dosage
  • Antidepressive Agents, Tricyclic / blood
  • Antidepressive Agents, Tricyclic / pharmacokinetics*
  • Area Under Curve
  • Cytochrome P-450 CYP2D6 / metabolism*
  • Cytochrome P-450 CYP2D6 Inhibitors*
  • Desipramine / administration & dosage
  • Desipramine / blood
  • Desipramine / pharmacokinetics*
  • Drug Administration Schedule
  • Drug Interactions
  • Duloxetine Hydrochloride
  • Female
  • Humans
  • Male
  • Middle Aged
  • Paroxetine / administration & dosage
  • Paroxetine / blood
  • Paroxetine / pharmacology
  • Reference Values
  • Serotonin Uptake Inhibitors / administration & dosage
  • Serotonin Uptake Inhibitors / blood
  • Serotonin Uptake Inhibitors / pharmacokinetics
  • Serotonin Uptake Inhibitors / pharmacology*
  • Thiophenes / administration & dosage
  • Thiophenes / blood
  • Thiophenes / pharmacokinetics
  • Thiophenes / pharmacology*


  • Antidepressive Agents, Tricyclic
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Serotonin Uptake Inhibitors
  • Thiophenes
  • Paroxetine
  • Duloxetine Hydrochloride
  • Cytochrome P-450 CYP2D6
  • Desipramine