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


Dr Yasufumi Sawada Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi 3–1-1, Higashi-ku, Fukuoka-shi 812–8582, Japan. Tel.: +81–92–642–6610, Fax: +81–92–642–6614.


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 publised 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.