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Effect of Amiodarone on the Serum Concentration/Dose Ratio of Metoprolol in Patients with Cardiac Arrhythmia

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Summary:

Amiodarone has pharmacokinetic interactions with a number of therapeutic drugs, including warfarin, phenytoin, flecainide, and cyclosporine. Metoprolol is mainly metabolized by CYP2D6, and desethylamiodarone, a metabolite of amiodarone, has a markedly greater inhibitory effect on CYP2D6 than amiodarone. Therefore, the goal of this study was to evaluate the effect of amiodarone and desethylamiodarone on the serum concentration/dose ratio (C/D) of metoprolol in 120 inpatients with cardiac arrhythmias that received either metoprolol and amiodarone (MET + AMD group, n = 30) or metoprolol alone (MET group, n = 90). The ratio of administered metoprolol was compared between the MET and the MET + AMD groups. The dose of metoprolol and patient age were significantly higher in the MET group when compared with the MET + AMD group (1.00 ± 0.480 versus 0.767 ± 0.418 mg/kg/ day, p<0.050; 68.6±10.6 versus 57.6±14.1 years, p<0.001, respectively), but the C/D ratio was significantly lower in the MET group than in the MET + AMD group (90.8 ± 64.0 versus 136 ± 97.8, p<0.01). Furthermore, a significant correlation was found between the C/D ratio and desethylamiodarone concentration (n = 30, r = 0.371, p<0.01). The results suggest that there is a significant interaction between amiodarone and metoprolol via desethylamiodarone-induced inhibition of CYP2D6. Therefore, careful monitoring of metoprolol concentrations/bioactivity of CYP2D6 is required in the context of co-administration of amiodarone and metoprolol.

References (49)

  • L.J. Lesko

    Pharmacokinetic drug interactions with amiodarone

    Clin. Pharmacokinet.

    (1989)
  • R. Latini et al.

    Clinical pharmacokinetics of amiodarone

    Clin. Pharmacokinet.

    (1984)
  • B.N. Singh

    Amiodarone: the expanding antiar-rhythmic role and how to follow a patient on chronic therapy

    Clin. Cardiol.

    (1997)
  • N.A. Estes et al.

    use of antiarrhythmics and implantable cardioverter-defibrillators in congestive heart failure

    Am. J. Cardiol.

    (2003)
  • K. Ohyama et al.

    Inhibitory effects of amiodarone and its N-deethylated metabolite on human cytochrome P450 activities: prediction of in vivo drug interactions

    Br. J. Clin. Pharmacol.

    (2000)
  • K. Ohyama et al.

    A significant role of human cytochrome P450 2C8 in amiodarone N-deethylation: an approach to predict the contribution with relative activity factor

    Drug Metab. Dispos.

    (2000)
  • L.J. Lesko

    Pharmacokinetic drug interactions with amiodarone

    Clin. Pharmacokinet.

    (1989)
  • L.D. Heimark et al.

    The mechanism of the interaction between amiodarone and warfarin in humans

    Clin. Pharmacol. Ther.

    (1992)
  • A.H. Watt et al.

    Amiodarone reduces plasma warfarin clearance in man

    Br. J. Clin. Pharmacol.

    (1985)
  • S. Almog et al.

    Mechanism of warfarin potentiation by amiodarone: dose-and concentration-dependent inhibition of warfarin elimination

    Eur. J. Clin. Pharmacol.

    (1985)
  • P.E. Nolan et al.

    Effect of phenytoin on the clinical pharmacokinetics of amiodarone

    J. Clin. Pharmacol.

    (1990)
  • P.E. Nolan et al.

    Pharmacokinetic interaction between intravenous phenytoin and amiodarone in healthy volunteers

    Clin. Pharmacol. Ther.

    (1989)
  • W.E. Haefeli et al.

    Potent inhibition of cytochrome P450IID6 (debrisoquine 4-hydroxylase) by flecainide in vitro and in vivo

    J. Cardiovasc. Pharmacol.

    (1990)
  • C. Funck-Brentano et al.

    Variable disposition kinetics and electrocardiographic effects of flecainide during repeated dosing in humans: contribution of genetic factors, dose-dependent clearance, and interaction with amiodarone

    Clin. Pharmacol. Ther.

    (1994)
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