Chronopharmacokinetic model analysis of 5-fluorouracil following S-1 administration in rats: comparison with infusion and other prodrugs for chronochemotherapy

Abstract

Circadian rhythms influence the pharmacokinetics of chemotherapeutic agents, including 5-fluorouracil, a cornerstone drug for colorectal cancer treatment. While chronomodulated chemotherapy for 5-fluorouracil infusion regimens can improve patient outcomes, the impact of circadian rhythms on oral 5-fluorouracil prodrug regimens remains poorly understood, and no dose-timing strategies have been established. This study investigated circadian variations in the pharmacokinetics of 5-fluorouracil after administering S-1, an oral fluoropyrimidine-based anticancer drug, in rats using a cosinor-based chronopharmacokinetic model. Plasma tegafur exposure showed significant circadian variation, peaking at 01:00 (17 h after light onset), whereas plasma 5-fluorouracil exposure exhibited no significant time-of-dosing differences. Chronopharmacokinetic analysis revealed minimal circadian variation in 5-fluorouracil clearance with S-1 (amplitude-to-mesor ratio: ±14.6 %) compared to long-term 5-fluorouracil infusion (±28.0 %) and other oral prodrugs including capecitabine (±43.0 %) and uracil-tegafur (±36.7 %), which showed pronounced fluctuations. These results suggest that S-1 provides consistent 5-fluorouracil exposure regardless of dosing time, offering a practical advantage by simplifying treatment schedules and reducing the need for chronomodulated therapy. This study could advance the development of 5-fluorouracil-based chronochemotherapy using oral prodrug regimens, enabling more personalized and effective cancer treatment strategies.