Disposition of Components of New Anti-cancer Drug S-1 (2): Distribution of Components of S-1 after Single Administration to Rats and Protein Binding

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.
After a single oral administration of [¹⁴C-FT]-S-1, [¹⁴C-CDHP]-S-1 or [¹⁴C-Oxo]-S-1 to rats, the tissue distribution of the radioactivity and the serum protein binding of FT, 5-FU, CDHP and Oxo were investigated in the present study.
1. In the experime nt on the tissue distribution of the radioactivity by direct counting method after administration of [¹⁴C-FT]-S-1 to male rats, the kidneys showed the highest while the white fat showed a low levels of radioactivity. According to whole body autoradiograms, the nasal cavity and eye ball (cornea and sclera) were found to show the high present of radioactivity.
2. In the experiment on the tissue distribution of the radioactivity by direct counting method after administration of [¹⁴C-FT]-S-1 to female rats, the distribution pattern of radioactivity in tissues except the genital organ was similar to that in male rats.
3. In the experiment on the tissue dist ribution of the radioactivity by direct counting method after administration of [¹⁴C-CDHP]-S-1 to male rats, the kidneys and digestive tract showed the highest radioactivity at early collection time points after administration. The elimination of the radioactivity from each tissues was rapid, and the levels of the radioactivity in the tissues and organs other than the large intestine decreased to the levels not more than 7% of the maximum concentrations at 24 hr after administration.
4. In the experiment on the tissue distribution of the radioactivity by direct counting method after administration of [¹⁴C-Oxo]-S-1 to male rats, the kidneys, liver, mesenteric lymph node and digestive tract showed the highest radioactivity at early data points after administration. A slow elimination of the radioactivity was observed in the white fat and brown fat, which showed originally low levels, but even at 72 hr after administration, showed the concentrations of about 50% of the maximum levels. The levels of the radioactivity in other tissues and organs decreased to the levels of 23% of the maximum levels, while at 72 hr after administration the levels in about half of tissues were below the detection limit. In the whole body autoradiograms prepared up to 24 hr after administration, a high radioactivity was observed in the periosteum and nasal cavity.
5. The ratios of serum protein binding of FT were 55.7-48.9% in human, 52.1-50.2% in dog and 42.9-40.7% in rat, and were higher than those ratios of other compounds in either animal species. The serum protein binding ratios of 5-FU, CDHP and Oxo were highest in human.