Lidocaine and Its Metabolites in Canine Plasma and Myocardium

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Abstract
Summary Lidocaine, a highly effective antiarrhythmic agent, is metabolized to monethylglycylxylidide (MEGX) and glycylxylidide (GX) by the liver in man. It readily suppresses ventricular arrhythmias but has little effect on atrial arrhythmias. Lidocaine was administered by a double infusion method to determine (a) whether these metabolites are formed in the dog; (b) if a time-dependent delay in myocardial lidocaine accumulation occurs; and (c) if the reported difference in antiarrhythmic effects might be due to a difference in myocardial uptake of lidocaine or its metabolites, MEGX and GX. Sixteen 10–15 kg pentobarbital-anesthetized dogs received lidocaine at 0.2 mg/kg/min for 5 min, followed by a 0.08 mg/kg/min infusion for either 1.5 (n = 8) or 6 h (n = 8). Levels of lidocaine, MEGX, and GX were determined by high performance liquid chromatography in the plasma at various times during the infusion, and in the left ventricle, right ventricle, left atrium, and right atrium at the end of the infusion. Mean plasma lidocaine concentration (±SEM) was 2.1 ± 0.2 μg/ml at the end of both the 1.5 and 6 h infusions, while mean concentrations of MEGX and GX significantly increased from 0.5 ± 0.1 to 1.1 ± 0.1 μg/ml (p < 0.001) and 0.8 ± 0.1 to 1.9 ± 0.2 μg/ml (p < 0.001), respectively, between the 1.5 and 6 h infusions. There were no significant differences in lidocaine or metabolite concentrations among cardiac chambers. Left ventricle/plasma ratios were not significantly different (2.6 ± 0.3 and 2.3 ± 0.2) for lidocaine at the end of the 1.5 and 6 h infusions; this was also true for MEGX and GX. These data demonstrate that (a) this model yields stable plasma and myocardial lidocaine levels over a prolonged infusion; (b) lidocaine metabolites accumulate over time in the dogs as in humans; and (c) there is no time-dependent delay in myocardial lidocaine accumulation when assessed between 1.5 and 6 h. In addition, the equal distribution of lidocaine and its metabolites in atria and ventricles suggests an alternative explanation for lidocaine's relative lack of effect on atrial as opposed to ventricular arrhythmias.