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Clinical Pharmacokinetics of Amiodarone

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Summary

Amiodarone is an iodinated benzofuran derivative with recognised antiarrhythmic activity in man. As yet, its pharmacokinetic behaviour has not been satisfactorily characterised. Specific and sensitive high-pressure liquid Chromatographic methods have become available only recently and this partly explains the scarcity of pharmacokinetic data on the drug.

Available evidence suggests that absorption of amiodarone following oral administration is erratic and unpredictable; oral bioavailability ranges from 22 to 86%. The drug is eliminated largely by metabolism; less than 1% of the dose is excreted unchanged in the urine. Biliary excretion may have a role in the overall elimination of the drug. Desethylamiodarone is the only metabolite positively identified in the plasma of patients receiving treatment with amiodarone; no data are available on its possible pharmacological activity.

Since it is a highly lipophilic drug, amiodarone is extensively distributed into tissues. Adipose tissue and skeletal muscle accumulate large amounts of the drug during long term treatment. Myocardium/plasma ratios of amiodarone are high both in man and in animals; peak concentrations in the myocardium are reached within half an hour after administration of an intravenous bolus to dogs. Placental transfer of amiodarone has been demonstrated in humans, while its blood profile is not modified by dialysis treatment. In vitro protein binding of amiodarone has been reported to be 96.3 ± 0.6%.

The plasma half-life of amiodarone after single-dose administration has been reported to be in the range of 3.2 to 79.7 hours. However, after withdrawal of long term amiodarone treatment the half-life is as long as 100 days. Total body clearance ranges from 0.10 to 0.77 L/min after single-dose intravenous administration, and the apparent volume of distribution ranges between 0.9 and 148 L/kg.

Amiodarone disposition kinetics in patients with cardiac arrhythmias are not different from those in healthy volunteers. However, the possible effects of liver and cardiac failure on the drug’s kinetics have not been studied.

Amiodarone potentiates the anticoagulant effect of warfarin, probably by inhibition of its metabolism. Increases of steady-state concentrations of digoxin, together with the appearance of signs of digitalis toxicity, have been reported when amiodarone was given to patients receiving long term treatment with digoxin. Amiodarone has also been shown to interact with other antiarrhythmic agents such as quinidine and procainamide.

The time of onset of action of amiodarone after a single intravenous dose ranges between 1 and 30 minutes and its duration of effect between 1 and 3 hours. During long term oral treatment, the therapeutic effect is observed after a delay of 2 to 21 days and can last more than 1 month after withdrawal of therapy. The time course of amiodarone electrophysiological effects after intravenous bolus administration to dogs follows its myocardial concentrations.

The plasma steady-state concentration of amiodarone found to be effective in man ranges from 0.4 to 11.99 μg/ml; however, even if no therapeutic range has yet been defined, there is good agreement on keeping steady-state levels between 1.0 and 2.5 μg/ml in patients treated for arrhythmias.

Clinically relevant extracardiac side effects have been reported, such as corneal deposits, thyroid dysfunction, peripheral neuropathy, pulmonary fibrosis and, less importantly, liver toxicity. Many of these side effects seem related to the dose and duration of amiodarone therapy, but information on their relationship to drug plasma concentrations is not available.

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  1. Laboratory of Clinical Pharmacology, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via Eritrea 62, Milano, 20157, Italy

    Roberto Latini, Gianni Tognoni & Robert E. Kates

  2. Division of Cardiology, Stanford University School of Medicine, Stanford, USA

    Roberto Latini, Gianni Tognoni & Robert E. Kates

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Latini, R., Tognoni, G. & Kates, R.E. Clinical Pharmacokinetics of Amiodarone. Clin Pharmacokinet 9, 136–156 (1984). https://doi.org/10.2165/00003088-198409020-00002

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