Additional Studies on Metabolism of WR-158,122 in Rats and Monkeys.

Abstract : Blood levels, excretion and tissue distribution of WR-158,122 14C were studied in 10 bile duct ligated rats, 10 bile duct cannulated rats, 8 control rats and in 2 control and one bile duct cannulated monkeys. In 72 hours bile duct ligated rats excreted about 16.3 + or - 3.8% as 14C in the urine and the remaining 14C was recovered primarily in the feces. About 2% was recovered in the carcass and tissues at necropsy. Bile duct cannulated rats excreted about 10.9 + or - 6.1% in the bile, 2.3 + or - 1.3% in the urine and the remainder in the feces. Only about 1.3 + or - 1.0% was recovered in the carcass and tissues. Control rats excreted the compound rather rapidly; 1.5 + or - 0.8% of the 14C was recovered in the urine, 0.3 + or - 0.2 in the carcass and other tissues and the remainder in the feces. Total average recovery (as 14C) in the three groups of rats varied from 94 to 100% of the dose. Two experiments were conducted in a single bile duct cannulated monkey. In the first the blood and plasma levels were highest at two hours after dosing. Plasma levels routinely exceeded levels in whole blood indicating little sequestration of WR-158,122 (as 14C) in the red cells. Both levels were low at 24 hours and below detection at 48 hours. In this bile duct cannulated monkey biliary excretion over a 96 h. period accounted for 0.6 to 0.9% of the dose (as 14C), urinary excretion for 3.1% and 87 to 95% of the dose was recovered in the feces. In two control monkeys urinary excretion over a 96 hour period amounted to 14 and 18%; 70% of the dose (as 14C) was recovered in the feces. Excretion was essentially complete after 96 hours. In both rats and monkeys WR-158,122 appears to be rapidly but incompletely absorbed.