Studies on the Disposition of Fadrozole Hydrochloride (CGS 1 6949A) (II): Absorption, Distribution, Metabolism and Excretion after Repeated Oral Administration to Rats.

The absorption, distribution, metabolism, and excretion of 14C-fadrozole hydorochloride (14C-CGS 16949A) were investigated during and after repeated oral administration to non-fasted female rats at a daily dose of 1mg/kg for 21days. 1. The levels of radioactivity in the plasma ( 24hr after daily dosing) reached a steady state after the 15th dosing and was 3. 1times higher than that found after the 1st dosing. The peak concentration (Cmax) and the half-lives after 21st dosing were 477ng eq. of CGS 16949 (the base of CGS 16949A)/ml and 10hr from 4hr to 24hr and 65hr from 48hr to 168hr. 2. The excretion ratio of radioactivity in the urine and feces reached a steady state after the 4th dosing and the excretion ratio after the 21st dosing was similar to that after single dosing. 3. The levels of radioactivity in the tissues after the 7th dosing increased in comparison with those after single dosing and the radioactivity levels after the 14th dosing were similar to those after the 7th dosing. The radioactivity in aorta after the 21st dosing was 8.9times higher than that after single dosing. 4. The relative amount of unchanged CGS 16949 in the plasma after the 21st dosing decreased and that of the metabolite with hydantoin type structure, MP2 increased, compared with those after single dosing. There were no significant differences between the concentration of CGS 16949 after single and the 21st dosing. 5. The relative amount of CGS 16949 and its metabolites in the urine for 24hours after 21st dosing was not significantly different from that after single dosing.