Pharmacokinetic analysis of felodipine-grapefruit juice interaction based on an irreversible enzyme inhibition model

Br J Clin Pharmacol. 2000 Jan;49(1):49-58. doi: 10.1046/j.1365-2125.2000.00140.x.


Aims Ingestion of grapefruit juice (GFJ) alters the pharmacokinetics of various orally administered drugs. Quantitative evaluation of this GFJ-drug interaction is required for the proper clinical management of patients. Methods Using felodipine as a model drug, we constructed a pharmacokinetic model based on irreversible inhibition of intestinal cytochrome P450 3A4 (CYP3A4) by GFJ. We fitted previously published data [5, 6] for felodipine ER (extended release formulation) to the ratio of CLGI,int before and after grapefruit juice ingestion by nonlinear least-squares regression analysis to estimate the reaction rate constant between GFJ and CYP3A4 (K) and the elimination rate constant of CYP3A4 (k ).

Results: The model gave a turnover rate of CYP3A4 of 0.0849 h-1, corresponding to a half-life of 8.16 h, in agreement with reported values. The AUC-time profiles of felodipine ER in the case of different amounts and schedules of GFJ ingestion were simulated using the parameter values estimated from the model.

Conclusions: The modelling leads to the important conclusion that GFJ-felodipine interaction increases with increasing frequency and amount of GFJ ingestion, and that an interval of 2-3 days between GFJ intake and felodipine administration is necessary if GFJ-felodipine interaction is to be avoided.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Area Under Curve
  • Beverages*
  • Biological Availability
  • Calcium Channel Blockers / pharmacokinetics*
  • Citrus*
  • Computer Simulation
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors / pharmacokinetics*
  • Felodipine / pharmacokinetics*
  • Food-Drug Interactions*
  • Gastrointestinal Transit / physiology
  • Humans
  • Intestinal Mucosa / metabolism
  • Liver / metabolism
  • Male
  • Metabolic Clearance Rate
  • Mixed Function Oxygenases / antagonists & inhibitors
  • Models, Biological


  • Calcium Channel Blockers
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Felodipine