Influence of Enhanced Alpha-1-acid Glycoprotein Concentration on Protein Binding, Pharmacokinetics and Antiarrhythmic Effect of Lidocaine in the Dog

The pharmacokinetics and the antiarrhythmic effect of lidocaine were studied in healthy dogs on three occasions: before administration of rifampicin, on the 14th day of treatment with rifampicin and 4 weeks after stopping rifampicin treatment. On each occasion a loading and a maintenance infusion of lidocaine were given to obtain steady-state concentrations. Blood and plasma concentrations of lidocaine, alpha-1-acid glycoprotein plasma concentrations and percentage of free lidocaine in plasma were determined at the end of the maintenance infusion. The antiarrhythmic effect of lidocaine was evaluated by measuring the arrhythmogenic dose of epinephrine. Blood concentrations and, consequently, the total blood clearance of lidocaine were comparable on the three occasions. Total plasma concentrations were significantly higher after rifampicin administration as compared to the two control periods. Percentage of free lidocaine decreased from about 50 to about 30%, accompanied by a nearly 3-fold increase of alpha-1-acid glycoprotein concentrations. Free plasma concentrations were slightly lower after rifampicin treatment. The epinephrine dose ratio (before/after) paralleled the changes in free lidocaine concentrations. The correlation between free plasma concentrations and epinephrine dose ratio was much stronger than between total plasma concentrations and epinephrine dose ratio. The plasma elimination half-life of lidocaine was markedly shortened after rifampicin treatment, due to a diminished volume of distribution. It is concluded that, under steady-state conditions, marked increases in the protein binding of lidocaine are accompanied by only slight decreases of free plasma concentrations and of antiarrhythmic effect.