Pharmacokinetic analysis of felodipine-grapefruit juice interaction based on an irreversible enzyme inhibition model.
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.
Takanaga
H
H
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka Prefecture, Japan.
Ohnishi
A
A
Matsuo
H
H
Murakami
H
H
Sata
H
H
Kuroda
K
K
Urae
A
A
Higuchi
S
S
Sawada
Y
Y
D000328:Adult; D019540:Area Under Curve; D001628:Beverages; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics*; D002957:Citrus; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D015736:Felodipine / Q000493:pharmacokinetics*; D018565:Food-Drug Interactions; D005772:Gastrointestinal Transit / Q000502:physiology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D008954:Models, Biological
D002121:Calcium Channel Blockers; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D015736:Felodipine