Inhibition by fluoxetine of cytochrome P450 2D6 activity

Clin Pharmacol Ther. 1993 Apr;53(4):401-9. doi: 10.1038/clpt.1993.43.

Abstract

Potent inhibition of cytochrome P450 2D6 (CYP2D6) in human liver microsomes by fluoxetine and its major metabolite norfluoxetine was confirmed (apparent inhibition constant values, 0.2 mumol/L). Several other serotonergic agents were also found to be competitive inhibitors of this genetically polymorphic enzyme. The O-demethylation ratio of dextromethorphan that expressed CYP2D6 activity in 19 patients receiving fluoxetine fell in the region of the antimode separating the O-demethylation ratio values observed in 208 extensive metabolizers from 15 poor metabolizers of a control group of healthy subjects. Inhibition of CYP2D6 activity in patients undergoing treatment with fluoxetine or other serotonin uptake inhibitors could contribute to toxicity or attenuated response from concurrent medications that are substrates of this enzyme. Other in vitro studies indicated that CYP2D6 catalyzes the O-demethylation of oxycodone to form oxymorphone. This reaction was inhibited by fluoxetine and its normetabolite in liver microsomes from both extensive and poor metabolizer individuals, indicating that these compounds are not selective inhibitors of CYP2D6 activity.

Publication types

  • Case Reports
  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Dextromethorphan / metabolism
  • Dextromethorphan / pharmacology
  • Drug Interactions
  • Fluoxetine / analogs & derivatives
  • Fluoxetine / metabolism
  • Fluoxetine / pharmacology*
  • Fluoxetine / therapeutic use
  • Humans
  • In Vitro Techniques
  • Male
  • Microsomes, Liver / drug effects*
  • Microsomes, Liver / enzymology
  • Middle Aged
  • Mixed Function Oxygenases / antagonists & inhibitors*
  • Mixed Function Oxygenases / genetics
  • Mixed Function Oxygenases / metabolism
  • Multiple Sclerosis / genetics
  • Oxidation-Reduction
  • Oxycodone / metabolism
  • Phenotype
  • Serotonin Uptake Inhibitors / pharmacology

Substances

  • Cytochrome P-450 Enzyme Inhibitors
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Dextromethorphan
  • Cytochrome P-450 Enzyme System
  • Oxycodone
  • Mixed Function Oxygenases
  • Cytochrome P-450 CYP2D6
  • norfluoxetine