Clinical Pharmacokinetics of Amiodarone

Abstract

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. Desethyl-amiodarone 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.(ABSTRACT TRUNCATED AT 400 WORDS)

Resting, and rate‐dependent depression of of guinea‐pig ventricular action potentials by amiodarone and desethylamiodarone

“…This finding is consistent with reports of higher levels of DEA than amiodarone in all tissues except fat in patients on chronic amiodarone therapy (Holt et al, 1983a,b;Latini et al, 1984).…”

“…This drug possesses very unusual pharmacokinetic properties including an extremely long biological half-life. It is metabolized in part to desethylamiodarone which frequently accumulates to higher concentrations than the parent compound during chronic dosage (Latini et al, 1984). Desethylamiodarone (DEA) possesses antiarrhythmic properties of its own (Nattel, 1983;Abdollah et al, 1986;Yabek et al, 1986).…”

Plasma protein binding of amiodarone in a patient population: measurement by erythrocyte partitioning and a novel glass‐binding method.

“…Adverse effects are common and can be severe, which limits the clinical usefulness of the drug. There is no simple relationship between dose and either therapeutic effect or toxicity (Heger et al, 1983;Latini et al, 1984), no doubt at least partly because of the drug's inconvenient pharmacokinetic characteristics. The oral bioavailability is erratic, it accumulates extensively in body tissues, and is only slowly eliminated from the body with a terminal half-life of weeks or months after long; term therapy (Sloskey, 1983;Latini et al, 1984).…”

Acute Renal Toxic Effect of Amiodarone in Rats

“…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 (Latini et al 1984 Only negligible amounts of the compounds were detected in urine (Harris et al 1983) and the disposition of amiodarone and its principal metabolite was similar in patients with normal renal function, moderate renal dysfunction and end-stage renal disease. Thus, dosage adjustment in patients with renal impairment is not necessary based on the pharmacokinetic analysis (Ujhelyi et al 1996).…”