Placental Transfer and Mammary Excretion of 1-(Bis(4-fluorophenyl)-methyl)-4-(2,3,4-trimethoxybenzyl)piperazine Dihydrochloride(KB-2796) in Rats.

Abstract

The placental transfer and mammary excretion of 1-[bis(4-fluorophenyl)-methyl]-4-(2, 3, 4-trimethoxybenzyl)piperazine dihydrochloride (KB-2796) were studied in rats after oral administration of 14C-labeled KB-2796. 1. The whole-body autoradiograms after oral administration to rats on the 13th day of pregnancy showed that the radioactivity in the fetus was higher than that in the placenta. 2. The maximum levels of radioactivity in the fetus were reached at 1 hr after administration to rats on the 18th day of pregnancy. The elimination of radioactivity in the fetus was slower than that in maternal plasma. The levels of radioactivity in the fetus at 48 hr was about 4 times higher than that in the mater nal plasma. In the fetus, radioactivity in the liver and lung was relatively higher than in other tissues, and the radioactivity in the lung was increasing up to 96 hr after the administration. 3. The maximum levels of radioactivity in the milk reached at 6 hr after the administration to lactating rats. The concentration is 37 times higher than that in the plasma. Thereafter, the concentration in the milk declined with half-life of 12.3 hr by 48 hr after dosing. The elimination was parallel to the plasma level. 4. The main metabolites of KB-2796 in the maternal and fetal lung were bis(4-fluorophenyl)methylpiperazine (M6) and 4, 4'-difluorobenzophenone (M10). 5. The unchanged KB-2796 accounted for about 60% of total radioactivity in the milk. 1-[Bis (4-fluorophenyl) methyl]-4-(3, 4-dimethoxy-2-hydroxybenzyl) piperazine (M2) and M10 were detected as the main metabolites in the milk.