Aaron Barchowsky

Lidocaine plasma protein binding

The percent of unbound lidocaine in the plasma of 24 healthy subjects was measured by equilibrium dialysis after addition of 3 µg/mlC14 lidocaine hydrochloride. The percentage of unbound lidocaine varied from 19.9 to 38.8 (30.2 ± 5, mean ± SD) and was inversely related to the concentration of α1–acid glycoprotein (AAG) in the plasma (r = −0.931, p < 0.001). The binding ratio (number of moles bound divided by number of moles unbound) of lidocaine was directly related to the plasma AAG concentration (r = 0.960, p < 0.001). The binding ratio of lidocaine in solutions containing AAG but no albumin, prepared from the plasma of subjects in the study, was also directly related to the concentration of this acute‐phase protein (r=0.909, p < 0.001). Human serum albumin solution (4 gm/100 ml) bound lidocaine to the extent of 20% under the same conditions. There was no relationship between the binding ratio of lidocaine and the albumin concentration in the plasma of the 24 subjects, in 7 normal subjects variation in AAG between 2 samples collected at least 2 mo apart was associated with a concomitant change in plasma lidocaine binding (r = 0.943, p < 0.01). Thus even in normal subjects there is considerable interindividual and intraindividual variation in lidocaine binding, and measurements of AAG concentration in plasma may be a useful predictor of the extent of lidocaine plasma binding.

Relationship between α1-acid glycoprotein and lidocaine disposition in myocardial infarction

The effects of myocardial infarction (MI) on lidocaine disposition were investigated in eight patients during a constant infusion of 2 mg/min. Plasma lidocaine binding and total plasma and free lidocaine concentrations were measured 12, 24, 36, and 48 hr after beginning therapy and were related to α1‐acid glycoprotein (AAG) concentrations. By 48 hr total plasma lidocaine and AAG concentrations had risen, as had plasma lidocaine binding. Because of enhanced binding, free lidocaine concentrations did not change significantly over this time. There was a correlation between AAG and the binding ratio for lidocaine (r = 0.87) and between AAG and total plasma lidocaine concentrations (r = 0.81). The data suggest that the rise in AAG seen after MI is responsible for enhanced plasma lidocaine binding and may, at least in part, be related to lidocaine cumulation.

Clinical comparison of rapid infusion and multiple injection methods for lidocaine loading.

A rapid infusion regimen for lidocaine loading (150 mg infusion over 18 minutes following a 75 mg priming injection) was evaluated in 12 patients. This was compared with multiple injection loading method in six patients involving three 50 mg injections over 18 minutes following the same priming dose. Both loading regimens were followed by a maintenance infusion of 2 mg/min. Predictably, the multiple injection method produced wide variations in lidocaine concentrations compared to the rapid infusion method. Some evidence of lidocaine toxicity (drowsiness, tinnitus) was seen in 13 of the 18 patients after the priming injection. During multiple injection loading, all six patients experienced side effects (drowsiness, tinnitus, dysarthria, or paresthesias.) Only 1 of 12 patients experienced a side effect (drowsiness) during rapid infusion loading. The difference in incidence of adverse reactions was significantly greater with the multiple injection regimen (p less than 0.01) but was associated with measurably greater drug levels.

Simultaneous determination of lidocaine and its metabolites in plasma and myocardium.

No validated method exists for measuring lidocaine and its metabolites in myocardial tissue. We modified a previously described high-performance liquid chromatographic assay and applied it to plasma and to homogenized myocardial samples obtained from dogs that had received lidocaine by a double-infusion technique. Recovery of lidocaine, monoethylglycylxylidide and glycylxylidide after homogenization and extraction is reported. Assay variability, sensitivity and linearity over a wide range of sample sizes are also described. The results obtained with high-performance liquid chromatographic analysis are compared to quantitation of 14C-labeled lidocaine plus metabolites measured by an oxidation-scintillation technique. Myocardium to plasma partition coefficients for lidocaine, monoethylglycylxylidide and glycylxylidide were 2.16, 4.27, and 2.91, respectively.

Lidocaine and Its Metabolites in Canine Plasma and Myocardium

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 lidocaines relative lack of effect on atrial as opposed to ventricular arrhythmias.