Studies on the Metabolic Fate of SS320A. (1): Absorption, Distribution, Metabolism, Excretion, Transfer into Fetus and Milk of 14C-SS320A after Single Administration in Rats.

Abstract

Absorption, distribution, metabolism, excretion, transfer into the fetus and milk were investigated after a single oral administration of 14C-SS320A 25 mg/kg to rats of both sexes. 1. The blood level of radioactivity in the fasting male rats reached the Cmax of 15.03 μg/ml at 0.31 hr and then declined with t1/2z of 5.7 hr. The AUC0-∞ was 33.0 μg hr/ml. In the blood, the parameters of radioactivity in the non-fasting rats were as follows, the Cmax values was lower, the Tmax and t1/2z were longer and the AUC was 1.3 times larger than those in fasting rats. The blood radioactivity in male and female rats were similar. 2. In a study of gastro-intestinal absorption in situ, the largest amount of 14C-SS320A was rapidly absorbed from the small intestine. 3. The all of tissues in the fasting male rats showed a maximum level of radioactivity at 0.5 hr after oral administration, and it was eliminated quickly until 24 hr. The high concentration of radioactivity was observed in the kidney, liver, cerebrum and eyeball. However, the radioactivity levels in these tissues were less than 1 % of the maximum level within 120 hr after administration. Also, in majority of tissues of non-fasting rats the T/P were similar, but, the elimination of radioactivity from tissues were slower than fasting rats. 4. The protein binding ratios (in vitro) of radioactivity were low in plasma sample of rats and human at0.2-20 μg/ml. In rats, the protein binding ratios (in vivo) of radioactivity were 4.0 and 2.5 % at 0.5 and 4 hr and then increased 19.5 % at 8 hr after oral administration. 5. The distribution ratio (in vitro) of radio activity in blood cells (fasting) of 14C-SS320A was about 28 and 35% in blood samples of rats and human, respectively, at 0.2-20 μg/ml. The distribution ratio of radioactivity in blood cells was about 25% from 0.5 hr to 8 hr after oral administration of 14C-SS320A to male rats. 6. In the urine M1 and M3 were mainly found. In the plasma the SS320A, M1, M3 and M4 were mainly found at 1 hr after oral administration of 14C-SS320A in fasting and non-fasting rats. M1 was found in cerebrum, eyeball and lung as the main metabolite in fasting rats, the unchanged form, however, was found mainly in liver and kidney. 7. In male rat, 96.8, 0.7 and 0.8% of the dose was excreted in the urine, feces and expired air, respectively, within 120 hr after oral administration of 14C-SS320A. The same results were obtained after intravenous administration. The sex differences in drug excretion were not observed. 8. The excretion of radioactivity in the bile, urine and feces in male rats was 1.3, 95.4 and 0.1% of the dose, respectively, within 48 hr after oral administration of 14C-SS320A. 9. On the 12-th and 18-th days of gestation, the level of radioactivity in the fetus after oral administration of 14C-SS320A was higher than that in maternal plasma. 10. The level of radioactivity in milk, after oral adm inistration of 14C-SS320A to lactating female rats on the 11-th day after delivery, was lower than that in plasma until 2 hr. Nevertheless, it reached the same concentration at 4 hr, and it was higher than that in plasma after 8 hr.