Dramatic inhibition of amiodarone metabolism induced by grapefruit juice

Authors

  • Christian C. Libersa,,

    1. Unité de Pharmacologie Clinique, Service de Pharmacologie Hospitalière, Faculté de Médecine, Université Droit et Santé, 1 Place de Verdun, 59045 Lille Cedex,
    2. Clinical Investigation Center CH&U – INSERM, Hôpital Cardiologique, Boulevard du Pr J. Leclercq,59037 Lille Cedex,
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  • Serge A. Brique,

    1. Clinical Investigation Center CH&U – INSERM, Hôpital Cardiologique, Boulevard du Pr J. Leclercq,59037 Lille Cedex,
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  • Kokou B. Motte,

    1. Unité de Pharmacologie Clinique, Service de Pharmacologie Hospitalière, Faculté de Médecine, Université Droit et Santé, 1 Place de Verdun, 59045 Lille Cedex,
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  • Jacques F. Caron,

    1. Unité de Pharmacologie Clinique, Service de Pharmacologie Hospitalière, Faculté de Médecine, Université Droit et Santé, 1 Place de Verdun, 59045 Lille Cedex,
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  • Laurence M. Guédon-moreau,

    1. Unité de Pharmacologie Clinique, Service de Pharmacologie Hospitalière, Faculté de Médecine, Université Droit et Santé, 1 Place de Verdun, 59045 Lille Cedex,
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  • Luc Humbert,

    1. Département de Biochimie – Toxicologie, Hôpital Calmette, Boulevard du Pr J. Leclercq,59037 Lille Cedex and
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  • A. Vincent,

    1. Unité de Pharmacologie Clinique, Service de Pharmacologie Hospitalière, Faculté de Médecine, Université Droit et Santé, 1 Place de Verdun, 59045 Lille Cedex,
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  • Patrick Devos,

    1. Délégation à la Recherche, CHRU, Boulevard du Pr J. Leclercq,59037 Lille Cedex, France
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  • Michel A. Lhermitte

    1. Département de Biochimie – Toxicologie, Hôpital Calmette, Boulevard du Pr J. Leclercq,59037 Lille Cedex and
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Professor Christian C. Libersa, CIC CHRU-INSERM, Hôpital Cardiologique, Boulevard du Pr. J. Leclercq, 59037 Lille Cedex, France. Tel.: (33)3.20.44.68.91; Fax: (33)3.20.44.68.90; E-mail: ciclille@chru-lille.fr.

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.

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