Metabolic Fate of a Benzoylphenylurea Derivative, HO-221. (II). Repeated Dosing Study and Metabolism in Rats.

The absorption, distribution and excretion of a benzoylphenylurea derivative, HO-221 were studied after repeated administration of 14C(Pc)-HO-221 once a day for a maximum of 28 days to male rats at a dose of 25 mg/kg. The radioactivity levels in the blood at 24 hr after daily dosing reached a steady state after the 20th dosing, being 2 times higher than after the 7th dosing. The radioactivity levels in all the tissues after the 28th dosing were less than 2 times of those after single dosing. The radioactivity was still detected at 240 hr after administration but only in the kidney and liver. The excretion of radioactivity in the urine and feces 24 hr after daily dosing did not change after the 4th dosing, and after the final repeated dosing was similar to that after single dosing. The metabolism was investigated after administration of 14C(Pc)-HO-221 or 14C(Pn)-HO-221 to male rats. The parent compound accounted for about 70% of the radioactivity in the plasma at 6 hr after administration. M5, M6, M7 and ο-nitrobenzamide were also detected in the plasma. The parent compound and M5 were principally observed in the liver, kid ney and fat. The conjugate of M6 was major metabolite in the urine, accounting for about 46% of the radioactivity in the urine. Unknown metabolites were major components in the bile. The parent compound and M5 were major in the feces. No difference was noted in urinary and fecal metabolites between the single and repeated dosing groups. UDPG transferase activity increased significantly by repeated dosing of HO-221.