Abstract
Absorption, distribution, metabolism and excretion of 14C-T-593 were investigated in rats after a single oral administration.
1. In the in situ loop study in rats, 14C-T-593 was widely absorbed from the duodenum to the colon.
2. The plasma levels of 14C T-593 after oral administration at doses of 10, 30 and 100 mg/kg to fasting male rats reached the Cmax within 0.31 ?? 0.63 hr, and thereafter declined bi-phasically. Both the Cmax and AUC0-∞ increased in linear proportion to the dose. In non-fasting rats, the Cmax and AUC0-∞ were about 38% and 90% of those in fasting rats, respectively. The absorbed amount of 14C-T-593 after oral administration was slightly decreased by the food intake. No difference was observed in the plasma concentration-time profile between male and female rats. The plasma levels of 14C-T-593 after intravenous administration at a dose of 10 mg/kg to male rats declined tri-phasically. The bioavailability was calculated to be about 9% compared the AUC0-∞ after oral and intravenous administration at a dose of 10 mg/kg.
3. The levels in most tissues after oral administration of 14C-T-593 at a dose of 10 mg/kg to fasting male rats reached the Cmax at 0.5 hr, and thereafter decreased in parallel with plasma level. The radioactivity in the testis was eliminated slowly compared with other tissues.
4. The radioactivity in the gastric mucosa after intraduodenal administration of 14C-T-593 at a dose of 10 mg/kg to fasting male rats was high followed by the muscular layer and plasma. The gastric mucosa maintained high level that decreased slowly.
5. Most of the radioactivity in the urine, bile and feces after oral administration of 14C-T-593 at a dose of 10 mg/kg to fasting male rats was the unchanged T-593, and T-593M1, M2, M3 and M5 were found in minor quantities.
6. Within 96 hr after oral administration of 14C-T-593 at a dose of 10 mg/kg to fasting male rats, the radioactivity excreted in the urine and feces were 2.5% and 98.9% of the dose, respectively. No difference was observed in urinary and fecal excretion between fasting and non-fasting rats, and also between male and female rats. Within 96 hr after intravenous administration of 14C-T-593 at a dose of 10 mg/kg to male rats, the radioactivity excreted in the urine and feces were 47.2% and 51.2% of the dose, respectively.
7. Within 24 hr after oral administration of 14C-T-593 at a dose of 10 mg/kg to bile supplied rats, the radioactivity excreted in the bile and urine were 8.4% and 31 YO of the dose, respectively.
8. The plasma concentration-time profile after intravenous and intraportal administration of 14C-T-593 at doses of 0.1, 1 and 10 mg/kg to male rats indicated that about 30% of the orally absorbed 14C T-593 was excreted into bile by the first pass effect.
