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A Comparison of Plasma, White Blood Cell, Red Blood Cell, and Tissue Distribution of Amiodarone and Desethylamiodarone in Anesthetized Dogs

Summary: Desethylamiodarone (DA) is a major metabolite of amiodarone (AM), a Class III antiarrhythmic drug. The plasma pharmacokinetics and tissue distribution of AM and DA (10 mg/kg i.v.) were compared in anesthetized dogs. Plasma, white blood cell (WBC), red blood cell (RBC), liver, and skeletal muscle samples were obtained at frequent intervals up to 6 h after a single i.v. bolus of the two drugs. Drug concentrations in these and other tissues, i.e., lung, kidney, heart (right and left atrium, right and left ventricle, Purkinje fibers, and AV node), and femoral nerve were measured by a highly sensitive and specific high-pressure liquid chromatographic technique developed in our laboratory. Four different patterns of AM and DA uptake and washout could be identified in these experiments. The first pattern is biex-ponential decline in plasma drug levels with a rapid distribution phase (t αt = 5.1 ± 2.1 min for AM and 5.5 ± 1.2 min for DA, respectively) and a slower elimination phase (t α = 3.7 ± 1.3 h for AM and 4.96 ± 0.8 h for DA, respectively). The volume of distribution of DA was significantly larger than that of AM. The second pattern is that both WBCs and RBCs showed an initial uptake within 5 min followed by a biexponential decrease in drug levels, with tβ similar to that in plasma but tα significantly longer than in plasma. In both these types of cells, the elimination half-life for DA was significantly longer than that of AM. The third pattern is that in the liver there was a rapid uptake of both drugs with peak concentrations at 15 min; the decline in hepatic levels of AM was biexponential, but that of DA appeared to be monoex-ponential. In addition, in dogs given AM alone, the metabolite (DA) was easily detected in the liver from the earliest time of measurement, suggesting that the parent drug is rapidly metabolized to DA. In the experiments where DA was injected, two new peaks were also identified in the liver suggesting that DA was metabolized further in the liver. The fourth pattern was in the skeletal muscle, where AM uptake was relatively slow, reaching peak concentrations between 1.5–2 h followed by a mono-exponential decline; however, DA was rapidly taken up by skeletal muscle, but the rate of decline appeared to be slower as compared to that of AM. Both drugs were found in all tissues examined at 6 h, and the rank order of concentration of AM was lungs > WBC > heart, liver, kidney > skeletal muscle > Purkinje fibers > AV node > RBCs. In the case of DA, the rank order of tissue concentration at 6 h was WBCs >> lung > heart, Purkinje fibers, liver, skeletal muscle, AV node > kidney > RBCs. It is concluded that although both AM and DA were widely distributed to many organs of the body, there are distinct differences in their pharmacokinetics, which may explain the differences in the rate of accumulation of the two drugs upon chronic therapy.