Alternative pharmacokinetics of S-1 components, 5-fluorouracil, dihydrofluorouracil and alpha-fluoro-beta-alanine after oral administration of S-1 following total gastrectomy.
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.
Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
Woo Young
WY
Kim
Bunzo
B
Nakata
Kosei
K
Hirakawa
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D004338:Drug Combinations; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D005743:Gastrectomy; D006801:Humans; D008875:Middle Aged; D010094:Oxonic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013274:Stomach Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000601:surgery / Q000652:urine; D005641:Tegafur / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015091:beta-Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics
D004338:Drug Combinations; D015091:beta-Alanine; C079198:S 1 (combination); D005641:Tegafur; C032348:alpha-fluoro-beta-alanine; D010094:Oxonic Acid; C019389:5-fluorodihydrouracil; D005472:Fluorouracil