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

UNLABELLED: 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.