PT  - JOURNAL ARTICLE
AU  - Kunihiro Yoshisue
AU  - Hirotoshi Masuda
AU  - Eiji Matsushima
AU  - Kazumasa Ikeda
AU  - Sekio Nagayama
AU  - Yasuro Kawaguchi
TI  - Tissue Distribution and Biotransformation of Potassium Oxonate after Oral Administration of a Novel Antitumor Agent (Drug Combination of Tegafur, 5-Chloro-2,4-dihydroxypyridine, and Potassium Oxonate) to Rats
DP  - 2000 Oct 01
TA  - Drug Metabolism and Disposition
PG  - 1162--1167
VI  - 28
IP  - 10
4099  - http://dmd.aspetjournals.org/content/28/10/1162.short
4100  - http://dmd.aspetjournals.org/content/28/10/1162.full
SO  - Drug Metab Dispos2000 Oct 01; 28
AB  - S-1, a new oral 5-fluorouracil (5-FU)-derivative antitumor agent, is composed of tegafur, 5-chloro-2,4-dihydropyridine, and potassium oxonate (Oxo). Oxo, which inhibits the phosphorylation of 5-FU, is added to reduce the gastrointestinal (GI) toxicity of the agent. In this study, we investigated the tissue distribution and the metabolic fate of Oxo in rats after oral administration of S-1. Oxo was mainly distributed to the intracellular sites of the small intestines in a much higher concentration than 5-FU, but little distributed to other tissues, including tumorous ones in which 5-FU was observed after oral administration of S-1. Plasma concentration-time profiles of Oxo and its metabolites after i.v. and oral administration of S-1 revealed that Oxo was mainly converted to cyanuric acid in the GI tract. Furthermore, the analysis of drug-related radioactivity in GI contents and in vitro studies suggested that Oxo was converted to cyanuric acid by two routes, the first being direct conversion by the gut flora in the cecum, and the second, conversion by xanthine oxidase or perhaps by aldehyde oxidase after degradation to 5-azauracil (5-AZU) by the gastric acid. These results indicate that, although a part of the administered Oxo was degraded in the GI tract, Oxo was mainly distributed to the intracellular sites of the small intestines in a much higher concentration than 5-FU and that little was distributed to other tissues, including tumors. We conclude that this is the reason why Oxo suppresses the GI toxicity of 5-FU without affecting its antitumor activity. The American Society for Pharmacology and Experimental Therapeutics