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

S-1, a new oral 5-fluorouracil (5-FU)-derivative antitumor agent, is compos ed of tegafur, 5-chloro-2,4-dihydropyridine, and potassium oxonate (Oxo). O xo, which inhibits the phosphorylation of 5-FU, is added to reduce the gast rointestinal (GI) toxicity of the agent. In this study, we investigated the tissue distribution and the metabolic fate of Oxo in rats after oral admin istration 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 d istributed to other tissues, including tumorous ones in which 5-FU was obse rved after oral administration of S-1. Plasma concentration-time profiles o f Oxo and its metabolites after i.v. and oral administration of S-1 reveale d that Oxo was mainly converted to cyanuric acid in the GI tract. Furthermo re, the analysis of drug-related radioactivity in GI contents and in vitro studies suggested that Oxo was converted to cyanuric acid by two routes, th e first being direct conversion by the gut flora in the cecum, and the seco nd, conversion by xanthine oxidase or perhaps by aldehyde oxidase after deg radation 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 intest ines in a much higher concentration than 5-FU and that little was distribut ed 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.