Studies on the Metabolic Fate of Flecainide Acetate. (1). Blood Levels, Distribution, Metabolism and Excretion in Rats after Repeated Intravenous Administration.

Abstract

Blood and plasma concentration-time profile, distribution, metabolism, excretion of radioactivity after a single intravenous administration of 14C-Flecainide acetate at a dose of 2 mg/kg to dogs, and in vitro and in vivo plasma protein binding were studied. 1. Plasma levels of radioactivity reached a maximal concentration at 0.5 hr after the dose, followed by a decrease with a half-life of 1.9 hr. The AUC(0-24hr) was 4.82μg eq.·hr/ml and the plasma level decreased to below the detection limit at 48 hr post dose. A maximal concentration of the unchanged flecainide was attained at 5 min, followed by a rapid decrease and by an increase of polar metabolites, including conjugates of meta-O-dealkylated flecainide and meta-O-dealkylated lactam of flecainide, which were found to be dominant in plasma. 2. Plasma protein binding (in vitro) of rat and dog was about 55% and 70%, respectively. The binding (in vivo) of radioactivity to dog plasma ranged from 30.7 to 47.7% during 0.5 to 4 hr after the dosing. 3. Radioactivity was distributed to many tissues and decreased to low level at 168 hr post dose, except for pigment ocular tissues in which radioactivity was distributed at a high level and was retained. In the heart, liver and kidney at 0.5 hr post dose, the unchanged flecainide, polar metabolites and meta-Odealkylated flecainide and meta-O-dealkylated lactam of flecainide were the main constituents of radioactivity and several other minor metabolites were also observed. 4. The excretion ratios of radioactivity into urine and feces were estimated to be 56.2 and 42.1% of the dose after 168 hr post dose, respectively. In urine, radioactivity was constituted mainly of polar metabolites which included conjugate metabolites of meta-O-dealkylated flecainide and meta-O-dealkylated lactam of flecainide.