s-1-(combination) and 5-fluorodihydrouracil

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Administration, Oral; Anti-Ulcer Agents; Antimetabolites, Antineoplastic; Area Under Curve; beta-Alanine; Biological Availability; Clinical Trials as Topic; Dihydrouracil Dehydrogenase (NADP); Drug Combinations; Fasting; Fluorouracil; Food; Gastric Acidity Determination; Half-Life; Humans; Hydrogen-Ion Concentration; Oxonic Acid; Pantoprazole; Pyridines; Tegafur; Triazines; Uracil

We studied whether total gastrectomy for gastric cancer would affect the pharmacokinetics of 5-fluorouracil (5-FU) and its degradation products, such as dihydrouracil (FUH(2)) and alpha-fluoro-beta-alanine (FBAL), after oral administration of the fluorouracil derivative S-1, composed of tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP; a dihydropyrimidine dehydrogenase inhibitor) and potassium oxonate. Blood and urine samples were obtained, both preoperatively and at least 2 weeks postoperatively, from six patients with advanced gastric cancers who were undergoing total gastrectomy. Plasma levels of tegafur, 5-FU, CDHP, potassium oxonate, FUH(2) and FBAL were measured prior to and at 1, 2, 4, 6 and 10 h after oral administration of 40 mg/m(2) S-1. The total amounts of 5-FU, FUH(2) and FBAL excreted into urine during the 24-h period after S-1 administration were also measured. Total gastrectomy significantly increased the maximum concentration and the area under the curve until 10 h after administration (AUC(1-10h)) of plasma 5-FU. The plasma AUC(1-10h) of CDHP was significantly higher than the preoperative value. In terms of clinical efficacy, the higher AUC(1-10h) of 5-FU after total gastrectomy may be beneficial to S-1 administered as adjuvant chemotherapy, and might be caused by the higher postoperative AUC(1-10h) of CDHP relative to preoperative values. However, the dose of S-1 for patients who have undergone total gastrectomy might be diminished to avoid severe adverse events and to continue the treatment for a long period.

Topics: Administration, Oral; Adult; Aged; Area Under Curve; beta-Alanine; Drug Combinations; Fluorouracil; Gastrectomy; Humans; Middle Aged; Oxonic Acid; Stomach Neoplasms; Tegafur