The systemic availability of 3H-lorcainide in rats was investigated following oral doses of 1.5 to 100 mg/kg. Systemic availability increased from 14 to about 40% following the lowest and highest dose, respectively. Doses higher than 60 mg/kg produced a less marked increase of the systemic availability. In rats with portacaval shunt following an oral dose of 1.5 or 7.5 mg/kg lorcainide a systemic availability of 47% was found, indicating substantial prehepatic first-pass metabolism of lorcainide. Systemic availability of total radioactivity was 53% in control rats and 90% in rats with portacaval shunt. Since the maximal systemic availability obtained by increasing the dose was found to be identical with that obtained in rats with portacaval shunt, it is suggested that increasing doses will saturate the presystemic metabolism in the liver but will not affect the fraction of the dose which is metabolized in the gut.