Studies on Metabolic Fate of 14C-RU44570: Placental Transfer, Transfer into Milk, Absorption Site and Repeated Dosing in Rats, and Metabolism in Rats and Dogs.

Abstract

The placental transfer, excretion into milk and site of absorption of 14C RU44570 were investigated in normal rats and male rats with ligated loops of gas trointestinal tract. The absorption, distribution, metabolism and excretion of 14C-RU44570 were examined during and after repeated oral administration to male rats at a daily dose of 1 mg/kg for 21 days. In addition, the metabolism of 14C-RU44570 in male dogs was studied after a single oral administration at a dose of 1 mg/kg. 1. In pregnant rats, receiving orally 1 mg/kg of 14C-RU44570 on the 18th days gestation, the level of radioactivity in fetus was lower than that in maternal plasma, and then ratio of the radioactivity was only 0.01% of the dose. In most of fetal tissues, the radioactivity levels decreased rapidly, however, relatively higher level was observed in the lung at 24 hr after the dosing. 2. The maximum concentration of radioactivity in the milk was found at 8 hr following oral administration of 14C-RU44570 at 1 mg/kg to lactating rats. The radioactivity concentration decreased with a half-life of 43 hr. 3. In a study of gastrointestinal absorption in situ, the most of 14C-RU44570 was found to be absorbed from duodenum and jejunum. 4. During repeated daily oral administration, plasma concentration of radioactivity at 24 hr did not increase significantly after the 7th dose. The elimination half-life of plasma radioactivity after the final dosing was comparable to that after the 1st dose. The radioactivity in most of tissues reached a steady state after the 7th or 14th dose during repeated administration. At 672 hr after the final dose, higher level of radioactivity was observed in the lung, while the concentration in other tissues decreased to lower level or even below the detection limit. 5. In plasma, urine, feces, bile or tissues, RU44403, which is a pharmacologically active form, was mainly found after both of single and repeated oral administration to male rats. Unchanged compound, RU44570, was not observed in plas ma and tissues. In addition, any conjugates of the metabolites were not found. 6. In plasma, urine or feces of male dogs, RU44403 was found as a major metabolite, however, RU44570 was also observed in dog plasma.