Minimal effective concentration values of propafenone and 5-hydroxy-propafenone in acute and chronic therapy

We evaluated the antiarrhythmic efficacy and the minimal effective concentrations of propafenone and its metabolite 5-hydroxy-propafenone during a) acute intravenous infusion (1.5 mg/kg in bolus followed by 45 minutes infusion), b) an acute oral single-dose test (450 mg), and c) 14-day chronic therapy (300 mg tid) followed by a washout. Oxidative metabolism was assessed by a debrisoquine oral test in every patient. Eleven patients with stable ventricular premature beats (VPBs) greater than or equal to 300/hr and Lown class greater than or equal to 3 completed the study. The main results emphasized a certain discrepancy between the clinical effect of the acute intravenous infusion (efficacy in 5 out of 11 patients) and of the acute oral test and chronic therapy (efficacy in 11/11), with a time lag of the ECG changes during the acute intravenous infusion. The minimal effective concentrations were lower after acute oral administration compared with chronic treatment both for propafenone (200 +/- 189 ng/ml vs. 492 +/- 530 ng/ml; p less than 0.05) and for 5-hydroxy-propafenone (82 +/- 40 ng/ml vs. 149 +/- 80 ng/ml; p less than 0.02). A linear correlation was demonstrated between drug/metabolite ratios of propafenone and debrisoquine, either after acute oral (r = 0.91) or after chronic administration (r = 0.84). The pharmacokinetics of propafenone was nonlinear and showed wide interindividual variations.