Alternative pharmacokinetics of S-1 components, 5-fluorouracil, dihydrofluorouracil and alpha-fluoro-beta-alanine after oral administration of S-1 following total gastrectomy

Abstract

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.

Figure 1

Chemical structure and catabolism of a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine S‐1.

Figure 2

Plasma concentrations of tegafur (FT) after oral administration of 40 mg/m² S‐1 in six patients. Closed circle, preoperative value; open column, value after total gastrectomy.

Figure 3

Plasma concentrations of 5‐fluorouracil (5‐FU) after oral administration of 40 mg/m² S‐1 in six patients. Closed circle, preoperative value; open column, value after total gastrectomy.

Figure 4

Plasma concentrations of 5‐chloro‐2,4‐dihydroxypyridine (CDHP) after oral administration of 40 mg/m² S‐1 in six patients. Closed circle, preoperative value; open column, value after total gastrectomy.

Figure 5

Plasma concentrations of potassium oxonate (OXO) after oral administration of 40 mg/m² S‐1 in six patients. Closed circle, preoperative value; open column, value after total gastrectomy.

Figure 6

Plasma concentrations of dihydrofluorouracil (FUH₂) after oral administration of 40 mg/m² S‐1 in six patients. Closed circle, preoperative value; open column, value after total gastrectomy.

Figure 7

Plasma concentrations of α‐F‐β‐alanine (FBAL) after oral administration of 40 mg/m² S‐1 in six patients. Closed circle, preoperative value; open column, value after total gastrectomy.