Studies on the Metabolic Fate of (.+-.)-2-(Dimethylamino)-1-((o-(m-methoxyphenethyl)-phenoxy)methyl)ethyl hydrogen succinate hydrochloride (MCI-9042). (III). Absorption, Distribution, Metabolism, Excretion, Accumulation and Effect on the Hepatic Drug-Metabolizing Enzyme Activities after Repeated Oral Administration to Rats.

Abstract

The absorption, distribution, metabolism, excretion and accumulation of MCI-9042 were investigated after repeated oral administration of 14C-MCI-9042 (20mg/kg/day) to male rats for 21 days. The effect of MCI-9042 on the hepatic drug-metabolizing enzyme activities was also investigated after repeated oral administration of MCI-9042 (20 or 100mg/kg/day) to male rats for 21 days. 1. The Tmax and Cmax of radioactivity in the blood after single oral administration to unfasted rats were delayed and decreased compared with those after single administration to fasted rats. Area under the time versus blood concentration curve (AUC0)∞ of radioactivity in unfasted rats was decreased about 18% compared with that in fasted rats. 2. Blood levels of radioactivity at 30 min after each dosing were nearly constant during repeated administration, and those at 24hr after each dosing were increasing up to the 12th day and then after reaching plateau remained constant. The half-life of blood levels of radi oactivity after 21 days repeated oral administration was 10.3hr (t1/2β), which was almost similar to that after single administration. 3.The tissue levels of radioactivity at 24hr after each dosing increased gradually till the 7th or 14th administration, and thereafter remaining at almost same levels. The tissue levels of radioactivity after 21 days repeated administration decreased gradually.4. The excretion rates of radioactivity into the urine and feces were nearly constant during the period of repeated administration of 14C-MCI-9042. Within 96hr after the last dosing, 21.8% and 74.3% of the administered radioactivity were recovered into urine and feces, respecti vely.5. The percentage of unchanged MCI-9042 and its metabolites to total radioactivity present in the plasma, liver, urine and feces after repeated administration were almost same as tho se after a single administration. 6. After repeated administration of MCI-9042 for 21 days, any effect on the hepatic micro somal drug-metabolizing enzyme system was not observed.