Pharmacokinetic study of S-1.

Since the first synthesis of 5-FU in 1957 fluoropyrimidines have been widely used clinically in the treatment of solid tumors. Because of good anti-tumor efficacy of 5-FU as a single agent on gastrointestinal tract tumors, many attempts have been made to develop new and superior 5-FU derivatives. Recently, S-1, a new antitumor medication based on the biochemical modulation of 5-FU, (1 M Tegafur (ftorafur, FT), 0.4 M 5-chloro-2, 4-dihydroxypyridine (gimeracil, CDHP), and 1 M potassium oxonate (oteracil, Oxo)) was developed. FT, which is a prodrug of 5-FU, plays a role as an effector. Both CDHP and Oxo, which do not have antitumor activity themselves act as modulators. CDHPcompetitively inhibits dihydropyrimidine dehydrogenase (DPD, EC 1.3.1.2), which in vitro degrades 5-FU about 180 times more effectively than uracil, leading to prolonged concentrations of 5-FU in blood. Oxo competitively inhibits pyrimidine phosphoribosyl transferase (EC 2.4.2.10), which converts 5-FU to 5fluorouridine 5’-monophosphate. Oxo is distributed primarily to the gastrointestinal tract after p.o. administration. This component of S-1 decreases the incorporation of 5-fluorouridine triphosphate into RNA in the gastrointestinal mucosa and reduces the incidence of diarrhea.