Disposition of Components of New Anti-cancer Drug S-1 (5): Transfer to Fetus and Milk of Components of S-1 in Rats

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 feto-placental transfer of the radioactivity and the excretion in the milk were investigated in the present study after administration of [14C-FT]-S-1, [14C-CDHP]-S-1 or [14C-Oxo]-S-1 to rats. 1. After administration of [14C-FT]-S-1 to the pregnant rats on day 12 of gestation, the f etus showed the maximum level of the radioactivity at 1 hr post-dose, accounting for 60% of the level of the radioactivity in maternal plasma. At 24 hr post-dose and thereafter, the levels of the radioactivity in the fetus were slightly higher than the levels in the maternal plasma but were not higher than 12% of the maximum levels. After administration of [14C-FT]-S-1 to pregnant rats on day 18 of gestation, the levels of the radioactivity in the whole fetus and each fetal tissues showed the maximum levels at 1 hr post-dose, which were 56-49% of the level of the radioactivity in the maternal plasma. At 48 hr post-dose, the levels of the radioactivity in the fetus and fetal tissues were almost same as or 3 times higher than maternal plasma levels but were equal or lower than 14% of the maximum levels. After administration of [14C-FT]-S-1 to lactating rats, the levels of the radioactivity in the milk showed the maximum level at 15 min post-dose, and decreased thereafter biphasically. At all data points, the levels in the milk were almost same as or lower than the plasma levels determined simultaneously. 2. After administration of [14C-CDHP]-S-1 to the pregnant rats on day 12 of gestation, the fetus showed the maximum level of the radioactivity at 1 hr post-dose, which was very low and corresponded to 5%of the level of the radioactivity found in maternal plasma. At 48 hr after administration, the level of the radioactivity in the fetus decreased to the level below the detection limit. After administration of [14C-CDHP]-S-1 to pregnant rats on day 18 of gestation, the levels of the radioactivity in the whole fetus and most of the fetal tissues showed the maximum levels at 1 hr post-dose, however, were very low and corresponded to 10-2 % of the levels of the radioactivity in the maternal plasma. At 48 hr after administration, the levels of the radioactivity in the fetus and fetal tissues decreased to the levels not more than 15% of the maximum levels. After administration of [14C-CDHP]-S-1 to lactating rats, the level of the radioactivity in the milk showed the maximum level at 1 hr post-dose, continued to stay at almost the same level during a period up to 4 hr post-dose, and decreased thereafter monophasically, reaching the level of the detection limit at 48 hr post-dose. At 4 hr after administration and thereafter, the levels in the milk were higher than the plasma levels determined simultaneously. 3. After administration of [14C-Oxo]-S-1 to the pregnant rats on day 12 of gestation, the fetus showed the maximum level of the radioactivity at 6 hr post-dose, and, thereafter, the concentrations were similar to the levels of the radioactivity in the maternal plasma during a period up to 48 hr after administration. After administration of [14C-Oxo]-S-1 to pregnant rats on day 18 of gestation, the levels of the radioactivity in all fetal tissues showed the levels similar to the levels of the radioactivity in the maternal plasma during a period from 6 hr to 24 hr post-dose