The effect of propafenone and its major metabolite 5-hydroxy-propafenone on ECG intervals was investigated in eight healthy extensive metabolizers after single oral (300 to 450 mg) and intravenous (35 to 50 mg) doses of propafenone in a single-blind randomized trial. Peak serum concentrations were 278 +/- 233 ng/ml (oral) and 295 +/- 131 ng/ml (intravenous). After oral administration peak 5-hydroxy-propafenone levels were 194 +/- 65 ng/ml, whereas after intravenous dosing no metabolite was detected, except in one subject. Serum concentrations were related to effects by linear regression including a hypothetical effect-site compartment in a pharmacokinetic-pharmacodynamic model. Significant prolongations of ECG intervals were found in both sequences. Comparison of the two concentration-effect data sets (intravenous, oral) revealed an additive effect of 5-hydroxy-propafenone in four of eight subjects for PQ interval and seven of eight subjects for QRS duration. We conclude that 5-hydroxy-propafenone exerts pharmacologic activity and could thus contribute to the antiarrhythmic effect of propafenone.