The effects of selective serotonin reuptake inhibitors and their metabolites on S-mephenytoin 4'-hydroxylase activity in human liver microsomes

Br J Clin Pharmacol. 1995 Nov;40(5):481-5. doi: 10.1111/j.1365-2125.1995.tb05793.x.


The inhibitory effects of four selective serotonin reuptake inhibitors (SSRIs), fluoxetine, sertraline, paroxetine and citalopram, and three metabolites (norfluoxetine, demethylcitalopram and didemethylcitalopram), on S-mephenytoin 4'-hydroxylation activities in human liver microsomes were studied. The 4'-hydroxylation of S-mephenytoin, a representative substrate toward CYP2C19, was competitively inhibited by all the SSRIs and their metabolites studied. The mean Ki values of fluoxetine, norfluoxetine, sertraline, paroxetine, citalopram, demethylcitalopram and didemethylcitalopram were 5.2, 1.1, 2.0, 7.5, 87.3, 55.8 and 7.7 microM, respectively. The findings suggest that some SSRIs and their metabolites with a low Ki value (e.g., fluoxetine, norfluoxetine) may reduce the clearance of drugs metabolized by this isoform of P450, thereby resulting in a possible drug-drug interaction, when administered simultaneously. In addition, SSRIs and their metabolites examined herein may be substrates toward CYP2C19.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aryl Hydrocarbon Hydroxylases*
  • Citalopram / pharmacology
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 Enzyme Inhibitors*
  • Fluoxetine / pharmacology
  • Humans
  • Kinetics
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology*
  • Mixed Function Oxygenases / antagonists & inhibitors*
  • Paroxetine / pharmacology
  • Selective Serotonin Reuptake Inhibitors / pharmacology*


  • Cytochrome P-450 Enzyme Inhibitors
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Citalopram
  • Paroxetine
  • Mixed Function Oxygenases
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19