Dramatic inhibition of amiodarone metabolism induced by grapefruit juice

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Abstract
Aims  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 µg ml−1 h, P < 0.005 and Cmax: 3.45 ± 1.7 vs 1.87 ± 0.6 µg 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.