Use of heterologously expressed human cytochrome P450 1A2 to predict tacrine-fluvoxamine drug interaction in man

Pharmacogenetics. 1998 Apr;8(2):101-8. doi: 10.1097/00008571-199804000-00002.


The aim of the present study was to evaluate the use of recombinant human cytochrome P-450 1A2 (rH-CYP1A2) in studies performed in vitro in order to predict metabolic drug-drug interactions occurring in man. In vitro metabolism of tacrine (a CYP1A2 probe) in the presence and absence of fluvoxamine, a CYP1A2 inhibitor, was investigated in human liver mircrosomes and with different rH-CYP. Vmax, Km and Ki determined with human liver microsomes were compared with those observed using rH-CYP1A2, assuming that 1 mg of liver microsomes contains, on average, 69 pmol of CYP1A2. The extent of tacrine metabolism inhibition procured by fluvoxamine with rH-CYP1A2, was compared with previous results observed in man. The Vax and Km for 1-hydroxytacrine formation rates obtained with rH-CYP1A2 were in good agreement with those observed in human liver microsomes (175+/-9 versus 140+/-60 pmol/min/mg for Vmax and 14+/-2 versus 16+/-2 microM for Km, respectively. The Ki of fluvoxamine on 1-hydroxytacrine formation rate observed with rH-CYP1A2 was similar to that observed with human liver microsome (0.35+/-0.05 versus 0.20+/-0.20 microM, respectively). Using the Km, Vmax and Ki determined with rH-CYP1A2, we calculated that fluvoxamine produced an inhibition of 1-, 2- and 4-hydroxytacrine formation rate of 91, 87 and 88%, respectively, in the range of tacrine and fluvoxamine concentrations observed in man. These percentages of inhibition calculated in vitro were in agreement with the percentage of fluvoxamine-dependent decrease in tacrine apparent oral clearance previously observed in man (83+/-13%). We conclude that human CYP1A2 expressed in yeast is a powerful tool to predict and to quantify drug-drug interactions in man.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antidepressive Agents, Second-Generation / metabolism
  • Antidepressive Agents, Second-Generation / pharmacology
  • Cytochrome P-450 CYP1A2 / genetics*
  • Cytochrome P-450 CYP1A2 / metabolism
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Drug Interactions
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Fluvoxamine / metabolism
  • Fluvoxamine / pharmacology*
  • Humans
  • Hydroxylation
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Nootropic Agents / metabolism
  • Nootropic Agents / pharmacology
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Tacrine / metabolism
  • Tacrine / pharmacology*


  • Antidepressive Agents, Second-Generation
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Enzyme Inhibitors
  • Nootropic Agents
  • Recombinant Proteins
  • Tacrine
  • Cytochrome P-450 CYP1A2
  • Fluvoxamine