Sematilide HCl is a novel class III antiarrhythmic drug. The goals of this study in volunteers were to determine the pharmacokinetics, effect (QTc interval), and tolerability after intravenous and oral administration of 25 mg of the drug. Plasma and urine concentrations were measured by a specific high-performance liquid chromatography method. Pharmacokinetic data analysis used a compartment model independent approach. An effect on QTc was observed only after intravenous administration, and its relationship to the plasma concentration showed a counterclockwise hysteresis. A semiparametric approach was used to collapse the hysteresis and then evaluate the effect-site-concentration-to-effect relationship. After intravenous and oral administration, 75.1 (6.5)% (mean ± SD) and 36.0 (11.5)% of the dose was excreted unchanged in urine, respectively. The respective renal clearances were 250 (41) ml ± min-1 and 222 (44) ml ± min-1. The bioavailability of sematilide was 0.47 (0.15). A maximum percent effect on QTc of 12 (1)% occurred with a delay of 14 min after termination of an intravenous infusion of 10 min. After collapsing the hysteresis, the pharmacokinetic-pharmacodynamic data could be fitted appropriately by a linear model in four subjects and by an Emax model in two subjects. Sematilide HCl was well tolerated.