Investigation of chronopharmacokinetics of capecitabine in mice

Circadian timing system modifies absorption, distribution, metabolism and elimination processes of drug pharmacokinetics over a period of approximately 24-hours. Depending on chronopharmacokinetics, exposure of target tissues to the active form of the drug and cytotoxicity display variations. For anticancer drugs with narrow therapeutic ranges and dose-limiting side effects, it is particularly important to know time dependent changes in pharmacokinetics. In our study, we aimed to evaluate circadian variations in pharmacokinetics of capecitabine and its metabolites. For this purpose, 500 mg/kg capecitabine was administered orally to C57BL/6J male mice at ZT1, ZT7, ZT13 or ZT19, and pharmacokinetics of capecitabine and 5'DFCR, 5'DFUR, 5-FU in plasma and liver were evaluated. In addition, time-dependent changes in capecitabine metabolising enzyme expressions were investigated. In our study, plasma Cmax and AUC0-6h values of capecitabine, 5'DFUR and 5-FU were higher during the rest span (ZT1 and ZT7) than the activity span (ZT13 and ZT19) (p<0.05). Similarly, Cmax and AUC0-6h values of 5'DFUR and 5-FU in liver were higher during the rest span than activity span (p<0.05), while there was no significant difference in liver concentrations of capecitabine and 5'DFCR. In addition, circadian rhythms were shown in CES1, CES2, CDA, UPP2 and DPD levels (p<0.05). Our findings show significant time-dependent changes in pharmacokinetics of capecitabine and its metabolites, and in capecitabine metabolizing enzyme levels. Our study, which reveals the circadian rhythms in the capecitabine pharmacokinetics with its mechanisms, contributes to the knowledge on the chronopharmacokinetics of anticancer drugs and supports the vital role of chronotherapy. Key Words: Capecitabine, chronopharmacokinetics, chronotherapy, cancer, circadian rhythms The present work was supported by the Research Fund of Istanbul University. Project No: TDK-2018-30939