Disposition of Components of New Anti-cancer Drug S-1(1): Absorption and Excretion of Components of S-1 after Single Administration to Rats.

Abstract

S-1, a new oral anti-cancer drug, is composed of tegafur(FT), gimestat(CDHP) and potassium otastat(Oxo) in a molar ratio of 1 : 0.4 : 1. FT which is masked compound of 5 fluorouracil (5-FU) plays a role as an effector. Both CDHP and Oxo which do not have anti-tumor activity themselves play roles as modulators.The absorption and excretion of the components of S-1 after administration of [14C-FT]-S-1, [14C-CDHP]-S-1 or [14C-Oxo]-S-1 to rats were investigated in the present study.1. After administration of [14C-FT]-S-1 to male rats under fasting condition, the blood levels of the radioactivity reached the Cmax value of 6215 ng eq./ml at 1 hr post-dose, and decreased thereafter biphasically. The main route of elimination was the urinary excretion. During a period up to 72 hr after administration, 74.7%, 1.6% and 15.5% of the dose administered were excreted in the urine, feces and expired air, respectively. In the bile, collected up to 48 hr after administration, 4.3% of the dose was excreted.2. In female rats administered with [14C-FT]-S-1 under fasting condition, the blood levels of the radioactivity and the excretion ratios did not differ much from those in fasted male rats.3. In male rats administered with [14C-FT]-S-1 under non-fasting condition, the food ingestion was demonstrated to show no effects on the absorption and excretion.4. The absorption ratios determined at 30 min after injection of [14C-FT]-S-1 to the loops of digestive tract were 96.0% in the duodenum, 96.2% in the jejunum, 91.4% in the ileum and 67.8% in the colon.5. After administration of [14C-CDHP]-S-1 to male rats under fasting condition, the blood leve ls of the radioactivity reached the Cmax value of 569 ng eq./ml at 1 hr post-dose, and decreased thereafter monophasically. The main route of elimination was the urinary excretion. During a period up to 72 hr after administration, 74.8%, and 22.5% of the dose administered were excreted in the urine and feces, respectively. In the bile, collected up to 48 hr after administration, 1.3% of the dose was excreted.6. Female rats administered with [14C-CDHP]-S-1 under fasting condition showed 1.3 times higher Cmax value and 1.4 times greater AUC value than those values in male rats, while the ratio of urinary excretion in female rats was lower than that in fasted male rats by 9.8%.7. In male rats administered with [14C-CDHP]-S-1 under non-fasting condition, the food ingestion was demonstrated to decrease the absorption ratio.8. The absorption ratios determined at 30 min after injection of [14C-CDHP]-S-1 to the loops of digestive tract were 18.2% in the duodenum, 20.2% in the jejunum, 12.1% in the ileum and 4.0% in the colon.9. After administration of [14C-Oxo]-S-1 to male rats under fasting condition, the blood levels of the radioactivity reached the Cmax value of 947 ng eq./ml at 1.3 hr post-dose, and decreased thereafter biphasically. The main route of elimination was the urinary excretion. During a period up to 72 hr after administration, 70.7%, 27.0% and 3.0% of the dose administered were excreted in the urine, feces and expired air, respectively. In the bile, collected up to 48 hr after administration, 1.0% of the dose was excreted.10. Female rats administered with [14C-Oxo]-S-1 under fasting condition showed 1.3 times higher Cmax value and 1.5 times greater AUC value than those values in male rats, while the ratio of urinary excretion in female rats was lower than that in fasted male rats by 16.6%.11. In male rats administered with [14C-Oxo]-S-1 under non-fasting condition, the food ingestion was demonstrated to cause the decrease in the absorption ratio and the marked change in the time course of the blood radioactivity.12. The absorption ratios determined at 30 min after injection of [14C-Oxo]-S-1 to the loops of digestive tract were 20.4% in the duodenum, 37.6% in the jejunum, 18.6% in the ileum and 6.8% in the colon.