Circadian variations in the pharmacokinetics of capecitabine and its metabolites in rats

Abstract

Capecitabine, an orally available prodrug of 5-fluorouracil, is widely used to treat patients with colorectal cancer. Although various studies have shown circadian variations in plasma 5-fluorouracil concentrations during long-term infusion, it is still unknown whether circadian variations also exist following administration of capecitabine. The present study aimed to investigate whether the pharmacokinetics of capecitabine and its metabolites, including 5-fluorouracil, vary according to administration time in rats. Rats were orally administered capecitabine (180mg/kg) at 07:00 (23h after light onset, HALO), 13:00 (5 HALO), or 19:00h (11 HALO). Plasma concentrations of capecitabine and its metabolites, such as 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), and 5-fluorouracil, were determined after capecitabine administration. The results showed that the t_1/2 and AUC_0-∞ values of 5-fluorouracil differed as a function of the dosing time of capecitabine. The maximum and minimum mean t_1/2 values of 5-fluorouracil were obtained when the drug was administered at 07:00h (23 HALO: 3.1±1.2h) and 13:00h (5 HALO: 1.5±0.6h), respectively. The AUC_0-∞ value of 5-fluorouracil at 07:00h (23 HALO: 533.9±195.7μmol∙h/L) was 1.8-fold higher than the value at 13:00h (5 HALO: 302.5±157.1μmol∙h/L). The clearance of 5-fluorouracil followed a cosine circadian curve, and the simulated population mean clearance was highest at rest times and lowest during active times in rats. The results for the plasma 5'-DFCR and 5'-DFUR levels indicated that circadian variations in the sequential metabolism of capecitabine to 5-fluorouracil would also affect plasma 5-fluorouracil levels following capecitabine administration. In conclusion, the pharmacokinetics of capecitabine and its metabolites, including 5-fluorouracil, varied according to time of dosing, suggesting that the capecitabine administration time is an important factor in achieving sufficient efficacy and reducing toxicity in patients.

Keywords: 5-Fluorouracil; 5′-Deoxy-5-fluorocytidine; 5′-Deoxy-5-fluorouridine; Capecitabine; Chronomodulated chemotherapy; Chronopharmacokinetics.