S-1, a new oral anti-cancer drug, is composed of 5-fluoro-1-(tetrahydro-2-furanyl)-2, 4(1
H, 3
H)-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) 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 compound. Both CDHP and Oxo which do not have antitumor activity themselves play roles as modulators. In this paper, species differences and dose-proportionality of S-1 components were investigated after a single administration of S-1 to mice, rats and dogs.
1. The pharmacokinetic parameter of FT, 5-FU, CDHP and Oxo in various animal species were obtained from mice, rats and dogs treated with S-1 (5 mg/kg as FT). C
max of FT was not different among any animal species. However, AUC of FT in dogs, rats and mice were 103, 155 ng·hr/m
l, 53, 600 ng·hr/m
l and 4, 180 ng·hr/m
l, respectively. These species differences were also shown in the case of half-lives of FT. The highest C
max of 5-FU among all species was in mice (1, 081 ng·hr/m
l), and the lowest was in rats (282 ng·hr/m
l). But half-life of 5-FU was smaller in mice than these in rats and dogs. C
max of CDHP in mice, 1, 815 ng·hr/m
l, was the highest in other species, however AUC of CDHP were not qualitatively different among mice, rats and dogs. C
max and AUC of Oxo were the highest in mice, and the lowest in rats.
2. The bioavailabilities of FT both in rats and dogs were approximately 100%. However, that of CDHP in rats and dogs were 36.8% and 27.0%, that of Oxo was 3.0% and 9.9%, respectively.
3. After oral administration (2, 5, 10 mg/kg as FT) of S-1 to dogs, AUC a nd C
max of the unchanged drug increased linearly, depending on dose escalation. But both C
max and AUC of 5-FU were more increased than dose escalation. We considered that this phenomenon was due to the higher inhibition of metabolism of 5-FU by CDHP at dose escalation.
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