Studies on the Disposition of Finasteride. (II). Absorption, Distribution, Excretion and Effects on Drug Metabolizing Enzyme System after Repeated Oral Administration to Rats.

Abstract

The absorption, tissue distribution and excretion of [14C]-finasteride were studied in male rats after repeated oral administration for 22 days at a dose of 5 mg/ kg/day. The effects of finasteride on the drug metabolizing enzyme system in male rats after repeated oral administration for 7 days were also investigated.1. A slight decrease in Tmax and increase in Cmax of the plasma radioactivity were observed after the final administration of [14C]-finasteride, as compared to those after the first administration. Furthermore, t1/2 and AUC values of the last dose were similar to those after the first dose, suggesting that both absorption and excretion rates do not change during the repeated administration.2. No change in the daily excretion of radioactivity in urine and feces was observed during the repeated dosing. Within 96 hr after the last dosing, urinary and fecal excretion of radioactivity were 1.7% and 88.5% of the administered dose, respectively, indicating that the main excretion route is fecal excretion.3. The levels of radioactivity were higher in all tissues at 24 hr after the last dosing than after the first dosing, particularly in fat pad which contained 61 times higher concentration. Although the radioactivity was generally eliminated slower from the tissues after the last dosing than from the plasma, no significant amount of radioactivity was accumulated in the tissues.4. Repeated oral administration of finasteride at doses of 5 and 80 mg/kg/day for 7 days did not have any effect on liver weight, microsomal protein concentration and drug metabolizing enzyme system, except that a moderate and significant increase in aniline p-hydroxylase activity was observed for the high dose group. However, this activity returned to the basal level at 1 week after the last administration.