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The absorption, distribution, metabolism, excretion and the effect on the drug-metabolizing enzyme activities of 1-[bis (4-fluorophenyl) methyl]-4 (2, 3, 4-trimethoxybenzyl) piperazine dihydrochloride (KB-2796) were studied in male rats during and after multiple oral administration at a dose of 2 mg/kg/day. 1. The blood radioactivities at 24 hr after daily administration increased progressively with an increase in the number of dosing, but remained practically constant after the 15th administration. 2. The blood radioactivity reached Cmax of 188.8 ng/ml at 8 hr after the 21st administration, and decreased gradually with the half-life of 67.3 hr. The Cmax and AUC after the 21st administration were 4.4 and 5.7 times greater than those after the 1st dosing, respectively. 3. The extents of cumulative excretion in the urine and feces were almost constant after the 15th administration, and those until 120 hr after the 21st administration were about 9 and 86%, respectively, which were similar with those after the 1st administration. 4. The radioactivity in tissues at 24 hr after daily administration increased with an increase in the number of dosing. After the final administration, a high level of radioactivity was observed in the fat, lung, liver, skin, adrenal and kidney. The elimination of radioactivity from tissues was slow, especially from the aorta. 5. The radioactivity in the brain, liver, lung, spleen, thymus and aorta were present predominantly in the unconjugated fraction. The main metabolites in the tissues were bis (4-fluorophenyl) methylpiperazine (M6) and 4, 4'-difluorobenzophenone (M10), and the unchanged drug was confirmed to be present in all their tissues. 6. The drug-metabolizing enzyme activities were increased after 7 day consecutive oral administration of KB-2796.

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Absorption, Distribution, Metabolism, Excretion and Effects on the Hepatic Drug Metabolizing Enzymes of 1-(Bis(4-fluorophenyl)methyl)-4-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride(KB-2796) after Multiple Oral Administration in Rats.