Dramatic inhibition of amiodarone metabolism induced by grapefruit juice.
OBJECTIVE
Grapefruit juice increases blood concentrations of many drugs metabolized by CYP3A. Amiodarone is metabolized by CYP3A to N-desethylamiodarone (N-DEA). The aim of this study was to determine amiodarone kinetics when administrated with and without grapefruit juice.


METHODS
Eleven healthy adult volunteers took part in a single sequence, repeated-measures design study. Each subject, who had been evaluated 6 months previously for amiodarone pharmacokinetics, was given a single oral dose of amiodarone (17 mg kg-1) with three glasses of 300 ml of grapefruit juice on the same day.


RESULTS
Grapefruit juice completely inhibited the production of N-DEA, the major metabolite of amiodarone, in all subjects and increased the area-under-the-curve (AUC) and maximum concentration of amiodarone (Cmax) by 50% and 84%, respectively, as compared with the control period during which water had been administrated instead of grapefruit juice (AUC: 35.9 +/- 14.3 vs 23.9 +/- 11.2 microg ml-1 h, P < 0.005 and Cmax: 3.45 +/- 1.7 vs 1.87 +/- 0.6 microg ml-1, P < 0. 02, respectively) (means +/- s.d.). This inhibition of N-DEA production led to a decrease in the alterations caused by amiodarone on PR and QTc intervals.


CONCLUSIONS
Grapefruit juice dramatically alters the metabolism of amiodarone with complete inhibition of N-DEA production. These results are in agreement with in vitro data pointing to the involvement of CYP3 A in the metabolism of amiodarone and suggests that this interaction should be taken into account when prescribing this antiarrhythmic drug.
Libersa
C C
CC
Unité de Pharmacologie Clinique, Service de Pharmacologie Hospitalière, Faculté de Médecine, Université Droit et Santé, 1 Place de Verdun, 59045 Lille Cedex, France. ciclille@chru-lille.fr
Brique
S A
SA
Motte
K B
KB
Caron
J F
JF
Guédon-Moreau
L M
LM
Humbert
L
L
Vincent
A
A
Devos
P
P
Lhermitte
M A
MA
D000328:Adult; D000638:Amiodarone / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D001628:Beverages; D001711:Biotransformation; D002957:Citrus; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004562:Electrocardiography / Q000187:drug effects; D018565:Food-Drug Interactions; D006207:Half-Life; D006801:Humans; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; C036116:desethylamiodarone; D000638:Amiodarone