Pharmacokinetics of S-1-two way biochemical modulation for enhancing 5-FU delivery into tumor and reducing GI toxicities

Abstract

S-1 is an oral form mixture of tegafur (FT) which produces 5-FU, 5-chloro-2, 4-dihydroxypyridine (CDHP) which inhibits 5-FU degradation and oxonic acid (Oxo) which reduces 5-FU toxicities, in a molar ratio of 1 : 0.4 : 1. Pharmacokinetics of S-1 were studied using tumor-bearing animals. Bioavailahility : AUCpo/AUCiv ratios of FT, CDHP and 5-FU in rabbits were almost 100% with some individual differences, while that of Oxo was 10% or less. The ratio showed a tendency to be higher in fasting animals than in feeding animals, especially in the case of 5-FU (P<0.05). CDHP and Oxo : In tumor-bearing rabbits and mice, CDHP was absorbed well and distributed at high levels in the GI tract and kidney, and detected at moderate levels in the liver, tumor and plasma. The most part of Oxo remained in the GI tract and it was also detected at a high concentration in the kidney, while at low in the liver, tumor and bone marrow. 5-FU following dose escalation of S-1 : S-1 was administered to tumor-bearing rats at doses of 2, 5, 10, 20 mg/kg. AUCs0∼24h of 5-FU were observed at the highest in the tumor in any dosing groups, in order of tumor>bone marrow>spleen>kidney>GI tract>liver and plasma. However, it was noticeable that AUCtumor/AUCplasma ratio rather decreased as the escalation of S-1 dose. The reason would be that 5-FU increased non-linearly in the plasma and most normal tissues following the dose escalation of S-1. Based on these data, the optimum dosage of S-1 in humans should be established to maximize the anticancer effects and minimize the adverse reactions. © 1996, THE JAPAN SOCIETY OF DRUG DELIVERY SYSTEM. All rights reserved.