Disposition of Components of New Anti-cancer Drug S-1 (4): Distribution of Components of S-1 after Repeated 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 modutators.
Repeated oral administration of [¹⁴C-FT]-S-1, [¹⁴C-CDHP]-S-1 or [¹⁴C-Oxo]-S-1 to male rats once daily for maximum 21 days was conducted, and the distribution of the radioactivity in the tissues and organs was investigated in the present study.
1. In the animal group admini stered with [¹⁴C-FT]-S-1 repeatedly, the tissue levels of the radioactivity at 24 hr after dosing increased with the number of administered doses, and showed a tendency to reach almost the steady state in all tissues and organs until the 21st dosing. The fat and brown fat showed the greatest increase in the levels, which were 15 times and 11 times higher, respectively, after the 21st dosing than after a single dosing. The increases of the levels in other tissues and organs after the 21st dosing did not exceed 7.4 times compared to the tissue levels after the single dosing. The tissue levels of the radioactivity after the 21st dosing declined slowly when compared to those in the animal group received the single administration (fasted male rats), and the levels of the radioactivity in the fat and femur were 46% and 27% of the maximum levels, respectively, at 504 hr after the 21st dosing. The levels in other tissues were not higher than 17% of the maximum levels.
2. In the animal group ad ministered with [¹⁴C-CDHP]-S-1 repeatedly, the tissue levels of the radioactivity at 24 hr after dosing did not show the increase associated with the number of doses. There was no difference in the tissue levels of the radioactivity at 1 hr post-dose between the animal group received the repeated (21 times) and the animal group received the single administration. The tissue levels in the animal group received repeated administration for 21 times decreased to the levels not exceeding 5% of the maximum levels at 168 hr after the final dosing, although the elimination of the radioactivity from the tissues was slightly slower than that in the animal group received the single dosing.
3. In the animal group administered with [¹⁴C-Oxo]-S-1 repeatedly, almost all of the tissue levels of the radioactivity at 24 hr after dosing increased along with the number of dose, and showed a tendency to further increase after the 21st dosing. The extents of the increase in the tissue levels were large after the first-7th dosing and small after the 14th-21st dosing. The fat and brown fat showed great increase in the levels, which were 16 times and 9.3 times higher, respectively, after the 21st dosing than after the single dosing.
The increases of the level in other tissues and organs after the 21st dosing were not more than 5.3 times compared to the tissue levels after the single dosing. The tissue levels of the radioactivity after the 21st dosing showed a slow elimination compared to those in the animal group received the single dosing, and the level of the radioactivity in the fat was 51% of the maximum level at 336 hr after the 21st dosing. The levels in other tissues were not more than 33% of the maximum levels.