Circadian variations in the pharmacokinetics of the oral anticancer agent tegafur-uracil (UFT) and its metabolites in rats

Abstract

Uracil-tegafur (UFT) is an oral anticancer drug containing uracil and 5‑fluorouracil prodrug tegafur and is widely used for adjuvant chemotherapy of colorectal cancer. Although clinical data show circadian variations in plasma 5‑fluorouracil concentrations during its long-term infusion, and feasibility studies of chronomodulated administration have been previously reported, the circadian pattern in plasma 5‑fluorouracil concentration after UFT administrations remains unclear. The aim of this study was to identify factors causing circadian variations in UFT pharmacokinetics and estimate circadian patterns of plasma 5‑fluorouracil concentration corresponding to UFT dosing time in rats. Rats were orally administered UFT (15 mg/kg as tegafur) at three different times of the day: 07:00 (23 h after light onset, HALO), 13:00 (5 HALO), or 19:00 (11 HALO), and then plasma concentrations of tegafur, 5‑fluorouracil, and uracil were measured after UFT administration. We found that the area under the plasma concentration-time curves (AUC_0-∞) of 5‑fluorouracil depended on the UFT dosing time of day with a 2.4-fold difference between the peak (at 19:00: 13.7 ± 1.4 μmol·h/L) and trough (at 13:00: 5.6 ± 1.3 μmol·h/L). The simulated population mean clearance of 5‑fluorouracil followed a 24-h cosine circadian curve, with the highest value in the early light phase being 2.2-fold higher than the lowest value in the early dark phase, which was an inverse circadian pattern compared to the plasma 5‑fluorouracil concentration. The plasma tegafur levels suggested that circadian variation in tegafur absorption and conversion to 5‑fluorouracil are factors causing variations in plasma 5‑fluorouracil levels following UFT administration. In conclusion, the circadian pattern of 5‑fluorouracil clearance and circadian variations in tegafur pharmacokinetics are important determinants of plasma 5‑fluorouracil concentrations following UFT administration. This knowledge could help in developing a chronomodulated administration strategy of UFT for improving clinical outcomes.

Keywords: 5‑Fluorouracil; Chronomodulated chemotherapy; Chronopharmacokinetics; Tegafur.