Pharmacokinetics, antiarrhythmic effects, and tissue concentrations of amiodarone and desethylamiodarone in dogs with acute coronary artery occlusion.

Abstract

A single bolus of 5 or 40 mg/Kg of amiodarone was injected 24 hours after inducing coronary artery occlusion in the closed-chest dog preparation. Plasma pharmacokinetic profile was determined and the calculated t1/2 beta of 3.5 +/- 2.8 and 3.2 +/- 0.6 hour after 5 or 40 mg/Kg dose, respectively, were obtained. The major metabolite, desethylamiodarone, was detected within 15 minutes of the single bolus of amiodarone. At 6 hours after amiodarone administration, the animals were killed and tissue concentrations of amiodarone and desethylamiodarone were measured. Two additional peaks in the HPLC chromatograms were observed in plasma and tissue samples of most dogs given 40 mg/Kg I.V. amiodarone and these most likely are due to unidentified metabolites of the drug. The highest drug concentration was found in the lungs. Tissue to plasma drug rations suggested that accumulation of amiodarone and perhaps desethylamiodarone was different for different tissues. Ventricular arrhythmias were not abolished by either of the two doses of amiodarone; however, there was a gradual and statistically significant decrease in the number of ventricular premature beats and ventricular tachycardia beats over the six-hour period after a single 40 mg/Kg I.V. bolus. At the time of reduction in the arrhythmia frequency, tissue levels of both amiodarone and desethylamiodarone in the border and infarct zone of the myocardium were approximately 50% as high as in the normal zone. Plasma drug levels did not correlate well with tissue concentrations. However, there was an excellent correlation between drug levels in WBCs and various tissues except the lung. It is concluded that amiodarone is rapidly metabolized into desethylamiodarone and at least two other unidentified compounds; a large dose of amiodarone is necessary to produce some decrease in ventricular arrhythmias associated with acute coronary artery occlusion; tissue concentrations may be better correlated with drug levels in WBCs than in plasma, and coronary artery occlusion does not affect acute pharmacokinetic profile of the drug.