Lorcainide; I. Saturable presystemic elimination

Abstract

The disposition of lorcainide after single oral and intravenous doses and during long‐term oral and intravenous dosing was investigated in 17 patients with chronic ventricular premature contractions. Lorcainide is thought to be eliminated mainly by metabolism in the liver. After a single intravenous (IV) dose of 2 mg/kg, the mean systemic clearance was 1.67 1/min, which is equal to the normal liver blood flow rate. When 10 of these patients were treated with 2 different single oral doses, the fraction of the dose reaching the systemic circulation (F) rose from a mean of 0.27 to 0.50 when the dose was increased from 150 to 300 mg. After long‐term oral dosing F increased further and approached unity in some patients. The plasma concentration of the N‐dealkylated metabolite rose and exceeded that of the parent drug when long‐term IV treatment was replaced by long‐term oral treatment. Simultaneous measurements of plasma concentration of lorcainide in the abdominal aorta and hepatic vein in 2 patients showed a high hepatic lorcainide uptake after a single IV dose. When 1 of these 2 patients was treated orally for 3 days (3 × 100 mg/day) concentration differences in afferent and efferent liver blood disappeared. Lung did not extract measurable amounts of lorcainide in 2 patients, in whom the plasma lorcainide concentrations were measured in the pulmonary artery and thoracic aorta over a period of 30 min after a single IV dose of 2 mg/kg. Our results suggest that lorcainide is subject to saturable presystemic elimination, most likely due to a saturation of hepatic extraction.