title: Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Lilly Laboratory for Clinical Research, Indiana University Hospital and Outpatient Center, 550 N. University Road, Indianapolis, IN 46202-5250, USA. skinner@lilly.com
authors.forename: Michael H
authors.initials: MH
authors.lastname: Skinner
authors.forename: Han-Yi
authors.initials: HY
authors.lastname: Kuan
authors.forename: Alan
authors.initials: A
authors.lastname: Pan
authors.forename: Korbtham
authors.initials: K
authors.lastname: Sathirakul
authors.forename: Mary Pat
authors.initials: MP
authors.lastname: Knadler
authors.forename: Celedon R
authors.initials: CR
authors.lastname: Gonzales
authors.forename: Kwee Poo
authors.initials: KP
authors.lastname: Yeo
authors.forename: Shobha
authors.initials: S
authors.lastname: Reddy
authors.forename: Maggie
authors.initials: M
authors.lastname: Lim
authors.forename: Mosun
authors.initials: M
authors.lastname: Ayan-Oshodi
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Wise
mesh_terms: D000328:Adult; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003891:Desipramine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D000068736:Duloxetine Hydrochloride; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017374:Paroxetine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D012016:Reference Values; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D013876:Thiophenes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000929:Antidepressive Agents, Tricyclic; D019389:Cytochrome P-450 CYP2D6; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003891:Desipramine; D000068736:Duloxetine Hydrochloride; D017374:Paroxetine; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes