K. Ikeda, H. Masuda, K. Yoshisue
Dec 31, 1997
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Journal
Drug Metabolism and Pharmacokinetics
Abstract
S-1, a new oral anti-cancer 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) 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). Cmax of FT was not different among any animal species. However, AUC of FT in dogs, rats and mice were 103, 155 ng·hr/ml, 53, 600 ng·hr/ml and 4, 180 ng·hr/ml, respectively. These species differences were also shown in the case of half-lives of FT. The highest Cmax of 5-FU among all species was in mice (1, 081 ng·hr/ml), and the lowest was in rats (282 ng·hr/ml). But half-life of 5-FU was smaller in mice than these in rats and dogs. Cmax of CDHP in mice, 1, 815 ng·hr/ml, was the highest in other species, however AUC of CDHP were not qualitatively different among mice, rats and dogs. Cmax 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 Cmax of the unchanged drug increased linearly, depending on dose escalation. But both Cmax 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.