P-35: Circadian and sex-dependent pharmacokinetics of everolimus and implications of chronotherapy
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The circadian clock system controls a variety of biological functions in mammals such as xenobiotic metabolism and detoxification. Circadian rhythms of biological functions may affect pharmacokinetics, toxicity and antitumor activity of anticancer agents. It is important to know dosing time-dependent pharmacokinetics of anticancer drugs that have high toxicity potential. The aim of our study was to investigate the effects of dosing time, gender and feeding status on the pharmacokinetics of anticancer drug everolimus. Everolimus (5 mg/kg, single dose) was administered to C57BL/6J male and female mice orally as fasted or ad libitum at two different times of the day (ZT1-rest and ZT13-active). Following drug administration, blood was collected, liver and ileum tissues were removed at six different time points (0.5, 1, 2, 4, 12, 24h). Everolimus was quantified by using HPLC-UV and pharmacokinetic parameters were calculated. We found that plasma Cmax of everolimus was lower in ZT1 male ad libitum mice group as compared to both ZT13 male and ZT1 female ad libitum mice and ZT1 male fasted groups (p<0.05). The same differences were observed between these groups for area under the curve (AUC0-24) values, which were indicative of the drug exposure. Everolimus concentrations in ileum were higher in all groups at ZT13 as compared to ZT1, which was more evident in fasted groups. On the contrary, liver exposure of everolimus was higher in all groups at ZT1 as compared to ZT13 and found to be statistically significant in ZT1 fasted male mice as compared to ZT13 fasted male mice (p<0.05). Higher liver exposure in ZT1 groups may indicate that everolimus leaves liver slower when administered at ZT1 as compared to ZT13. In conclusion, pharmacokinetics of everolimus may vary depending on dosing time, gender and feeding status. The temporal variations in everolimus pharmacokinetics, especially for the liver data, need to be discussed by integrating chronopharmacodynamics of everolimus for better understanding of this chronopharmacological phenomena. Our findings indicate that it is important to assess the everolimus chronotherapy for safer and more effective therapy in humans in future studies. Keywords: Everolimus, chronopharmacokinetics, circadian clocks, chronomodulated chemotherapy. This study was supported by TÜBİTAK 216S475 and Research Fund of Istanbul University 24831.