Fluvoxamine-theophylline interaction: gap between in vitro and in vivo inhibition constants toward cytochrome P4501A2

Clin Pharmacol Ther. 2001 Nov;70(5):415-24. doi: 10.1067/mcp.2001.119724.


Objective: Several reports indicate that fluvoxamine decreases the clearance of cytochrome P4501A2 (CYP1A2) substrates. This study compared in vitro and in vivo inhibition potencies of fluvoxamine toward CYP1A2 with an approach based on inhibition constants (K(i)) determined in vitro and in vivo.

Methods: In vitro inhibition constant values were determined with human liver microsomes and complementary deoxyribonucleic acid-expressed CYP1A2 (supersomes). Fluvoxamine in vivo inhibition constants (K(i)iv) for CYP1A2 were obtained from an investigation of single-dose theophylline (250 mg) disposition in 9 healthy volunteers receiving steady-state (9 days) fluvoxamine at 3 doses (0, 25, or 75 mg/d) in a randomized crossover design.

Results: In vitro K(i) values based on total inhibitor concentrations were 177 +/- 56 nmol/L, 121 +/- 21 nmol/L, and 52 +/- 13 nmol/L in human liver microsomes with 1 mg/ml protein and 0.5 mg/ml protein and in supersomes with 0.3 mg/ml protein, respectively. The corresponding in vitro K(i) values based on unbound fluvoxamine concentrations were 35 nmol/L, 36 nmol/L, and 36 nmol/L. The ratio of 1-methyluric acid formation clearances (control/inhibited) in 8 subjects was positively correlated with fluvoxamine concentration (r (2) = 0.87; P <.001) with an intercept near 1. Mean values for K(i)iv based on total and unbound plasma concentrations at steady state were 25.3 nmol/L (range, 14-39 nmol/L) and 3.6 nmol/L (range, 2.4-5.9 nmol/L), respectively.

Conclusion: Comparison of in vitro and in vivo K(i) values based on unbound fluvoxamine concentrations suggests that fluvoxamine inhibition potency is approximately 10 times greater in vivo than in vitro.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Cross-Over Studies
  • Cytochrome P-450 CYP1A2 Inhibitors*
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology*
  • Fluvoxamine / metabolism
  • Fluvoxamine / pharmacology*
  • Humans
  • In Vitro Techniques
  • Theophylline / pharmacokinetics*


  • Cytochrome P-450 CYP1A2 Inhibitors
  • Enzyme Inhibitors
  • Theophylline
  • Fluvoxamine