Absorption, distribution and excretion of 1-(bis(4-fluorophenyl)methyl)-4-(2,3,4-trimethoxybenzyl) piperazine dihydrochloride (KB-2796) after single oral administration in rats.

Abstract

The absorption, distribution and excretion of KB-2796 were studied in male and female rats after single oral administration of [14C] KB-2796.1. Maximum blood concentration of radioactivity appeared at 1hr after administration to male rats at a dose of 2mg/kg and the secondary peak occurred at 12hr after dosing. Thereafter blood concentration decreased with the terminal half-life of 42.9hr. The blood concentrations were increased proportionally to the administered doses ranging from 2mg/kg to 20 mg/kg. The blood concentrations in female rats decreased more slowly than that in male rats with a terminal half-life of 79.4hr.2. Male rats excreted 67.4% of the dose in bile and 6.4% of the dose in urine within 48 hr after dosing and 5.7% of the dose remained in the carcass. The absorption rate from the intestinal tract was assumed to be about 80%. The radioactivity was mainly excreted in feces via bile and partly underwent enterohepatic circulation. The biliary excretion in female rats was lower than that in male rats and the radioactivity was slowly eliminated from the body.3. Tissue concentrations of radioactivity were over 3 times higher than the plasma concentration except for the concentrations in the blood and eyeball at 6hr after administration to male rats. The high radioactivity was found in the lung, liver and fat, and disappeared slowly from tissues. Tissue concentrations in female rats were higher than those in male rats.4. The plasma protein binding in vitro was independent of the concentration (0.04-1μg/ml), and was about 60% in rats and 80% in human. In vivo study, 69.5-82.0% of radioactivity was bound to protein of male rat plasma collected 1hr to 24hr after administration.