OBJECTIVES: The anti-tumour agent S-1 comprises tegafur (a prodrug of 5-fluorouracil; 5-FU), gimeracil (2-chloro-2,4-dihydroxypyridine (CDHP); a competitive inhibitor of 5-FU metabolism) and oteracil potassium. The effect of hepatic dysfunction induced by dimethylnitrosamine (DMN) on the pharmacokinetics of 5-FU after administration of S-1 to rats was investigated. METHODS: S-1 (5 mg/kg) was administered intravenously and orally to rats with DMN-induced liver dysfunction. Plasma concentrations of S-1 components and 5-FU were measured by HPLC and LC/MS-MS. Blood tests and in-vitro enzymatic investigations were also conducted. KEY FINDINGS: DMN treatment induced hepatic dysfunction and decreased the conversion of tegafur to 5-FU in the liver without altering renal function or dihydropyrimidine dehydrogenase activity. Following intravenous administration of S-1, the blood concentration-time profiles of CDHP were similar between control rats and rats with hepatic dysfunction, but the half-life of tegafur was significantly prolonged. The maximum plasma concentration (C(max)) of 5-FU was significantly reduced and the area under the blood concentration-time curve (AUC) was reduced by 22%. Following oral administration, the C(max) of tegafur, 5-FU and CDHP were significantly decreased and half-lives significantly increased. Hepatic dysfunction had a less pronounced effect on the AUC of 5-FU (13.6% reduction). CONCLUSIONS: The pharmacokinetic profiles of tegafur, 5-FU and CDHP were altered by changes in the elimination rate of tegafur induced by a decrease in the conversion of tegafur to 5-FU. However, hepatic dysfunction had less of an effect on the AUC of 5-FU, which correlates with anti-tumour effect, after the oral administration of S-1.
OBJECTIVES: The anti-tumour agent S-1 comprises tegafur (a prodrug of 5-fluorouracil; 5-FU), gimeracil (2-chloro-2,4-dihydroxypyridine (CDHP); a competitive inhibitor of 5-FU metabolism) and oteracil potassium. The effect of hepatic dysfunction induced by dimethylnitrosamine (DMN) on the pharmacokinetics of 5-FU after administration of S-1 to rats was investigated. METHODS: S-1 (5 mg/kg) was administered intravenously and orally to rats with DMN-induced liver dysfunction. Plasma concentrations of S-1 components and 5-FU were measured by HPLC and LC/MS-MS. Blood tests and in-vitro enzymatic investigations were also conducted. KEY FINDINGS:DMN treatment induced hepatic dysfunction and decreased the conversion of tegafur to 5-FU in the liver without altering renal function or dihydropyrimidine dehydrogenase activity. Following intravenous administration of S-1, the blood concentration-time profiles of CDHP were similar between control rats and rats with hepatic dysfunction, but the half-life of tegafur was significantly prolonged. The maximum plasma concentration (C(max)) of 5-FU was significantly reduced and the area under the blood concentration-time curve (AUC) was reduced by 22%. Following oral administration, the C(max) of tegafur, 5-FU and CDHP were significantly decreased and half-lives significantly increased. Hepatic dysfunction had a less pronounced effect on the AUC of 5-FU (13.6% reduction). CONCLUSIONS: The pharmacokinetic profiles of tegafur, 5-FU and CDHP were altered by changes in the elimination rate of tegafur induced by a decrease in the conversion of tegafur to 5-FU. However, hepatic dysfunction had less of an effect on the AUC of 5-FU, which correlates with anti-tumour effect, after the oral administration of S-1.