Pharmacokinetics and the antiarrhythmic effect of mexiletine in patients with chronic ventricular arrhythmias.

A new antiarrhythmic agent, 1-(2,6- dimethylphenoxy )-2-aminopropane (mexiletine), was investigated in 10 patients with chronic premature ventricular contractions (PVCs) to evaluate the antiarrhythmic efficacy and the pharmacokinetics after single intravenous, single oral and repeated oral dosings of mexiletine 150 mg. Mexiletine was well absorbed from the intestinal tract. The relative bioavailability was 83.2 +/- 8.9% (mean +/- S.E.). The time-concentration curve of mexiletine fitted in well with two-compartment open model. Elimination half-life, volume of distribution and plasma clearance were 10.54 +/- 0.26 h, 2.10 +/- 0.49 l/kg, 6.01 +/- 0.63 ml/min/kg, respectively. The computer-simulated time-concentration curves of multiple oral dosings , which were based on the kinetic parameters from single oral dosing, conformed well with measured concentrations. This might be applied to predict the plasma level of mexiletine. The steady state of plasma mexiletine level was reached 4-5 days after 450 mg/day dosings and ranged 0.75-2.18 micrograms/ml. In 6 of 10 patients, the frequency of PVCs was suppressed more than 75% as compared with the pre-medication value. Mexiletine was well tolerated at a dose of 450 mg/day. However, of 4 patients with the dose increased to 600 mg/day, the administration was ceased in three patients due to gastrointestinal symptoms and tremor. All of these adverse reactions disappeared when the administration was stopped. These results suggest that mexiletine is effective against ventricular arrhythmias and the dosage should be carefully adjusted. The prediction of plasma level would be applied to the dosage regimen of mexiletine.