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.