Abstract
Blood concentration-time profile, distribution, metabolism and excretion of radioactivity were studied after repeated intravenous administration of 14C-flecainide acetate at a dose of 5 mg/kg/day for 7 days to rats.
1. Blood concentration-time profile of radioactivity on the 7th day was similar to that on the 1st dose and blood levels of radioactivity were not affected by repeated administration. In the plasma, concentration of the unchanged flecainide was decreased rapidly after the dosing with simultaneous increase of polar metabolites with time. Little change of flecainide/radioactivity concentration ratio in plasma was observed between 1st and 7th dose.
2. Radioactivity was well distributed to many tissues with a relatively high level compared to the plasma. Total radioactivity in tissues and corresponding tissue to plasma concentration ratios after 7th repeated administration were similar to those after the single dose. These tissue levels of radioactivity decreased with time and reached low level at 168 hr and 504 hr after the final dose. In the heart, liver and kidney, the radioactivity constituted mainly of the unchanged flecainide.
3. The excretion ratio for cumulative dose of radioactivity into the urine and feces showed constant throughout the period of repeated administration. At 168 hr after final dosing, 41.5%, 55.6% and 0.2% of a cumulative dose was recovered in urine, feces and carcass, respectively. In these excreta, the unchanged flecainide, meta-O-dealkylated flecainide and meta-O-dealkylated lactam of flecainide, and conjugated metabolites were dominant.
