Disposition of Components of New Anti-cancer Drug S-1 (7): Metabolism of Components of S-1 after Administration to Tumor bearing Rats.

Abstract

1. S-1, a new oral anti-tumor drug, is composed of 5-fluoro-1-(tetrahydro-2-furanyl)-2, 4(1H, 3H)-pyrimidinedione (Tegafur, FT), 5-chloro-2, 4-dihydroxypyridine (Gimestat, CDHP) and potassium 1, 2, 3, 4-tetrahydro-2, 4-dioxo-1, 3, 5-triazine-6-carboxylate(potassium otastat, Oxo) at a molar ratio of 1 : 0.4 : 1. FT which is masked compound of 5-Fluorouracil (5-FU) plays a role as an effector compound. Both CDHP and Oxo which do not have antitumor activity themselves play roles as modulators. After administration of S-1 or FT to tumor bearing rats, the Cmax and AUC of 5-FU were 20.8 pmol/ml and 207.6 pmol·hr/ml, in FT group and 1, 192.0 pmol/ml and 5, 203.0 pmol·hr/ml, in S-1 group. Thus, the S-1 group showed higher plasma 5-FU levels by 57 times in Cmax and by 25 times in AUC than those in the FT group. Similar to the plasma concentration, the concentration of 5-FU in tumor in the S-1 group was also higher than that in the FT group by 23 times in Cmax and by 16 times in AUC. 2. After administration of S-1 to tumor bearing rats, the plasma concentratio n of CDHP, the reversible competitive inhibitor of dihydropyrimidine dehydrogenase (EC1.3.1.2), showed a Cmax value of 2, 054.8 pmol/ml at 30 min post-dose. The concentration of Oxo, the inhibitor of orotate phosphoribosyltransferase (EC2.4.2.10), in small intestine showed a Cmax value of 36, 156.5 pmol/g at 30 min post-dose, and showed still high concentration of 2, 813.6 pmol/g even at 3 hr post-dose. 3. AUC of 5-FU in plasma and various tissues after a dministration of S-1 were found to be greater than those AUC after administration of UFT (combination of FT and uracil). AUC of fluoroureidopropionic acid (FUPA) and fluoro-β-alanine (FBAL) in the S-1 group were smaller than those in the UFT group.