Chronopharmacokinetics of MTOR inhibitor everolimus in mice

Circadian timing system controls drug pharmacokinetics including absorption, distribution, metabolism/detoxification and elimination. Chronopharmacokinetics are especially important for anticancer drugs with narrow therapeutic index and high inter-individual variability. The aim of our study was to investigate effects of dosing-time (ZT1-rest/ZT13-activity), sex and feeding on everolimus pharmacokinetics. Everolimus (5mg/kg, single-dose) was administered orally to C57BL/6J male/female, fasted/fed mice at ZT1 and ZT13, and pharmacokinetic parameters were evaluated. Additionally, P-glycoprotein levels were measured in everolimus (5mg/kg, 14-days)- or vehicle-treated male/female mice at ZT1/ZT13. Plasma Cmax, AUC0-24 and AUCtotal were higher at ZT13 than ZT1 in all groups. In liver, everolimus levels were significantly higher at ZT1 than ZT13 (p<0.05). In males, distribution of everolimus to liver was increased in fasting. Ileum concentrations were higher in fed mice compared to fasted and were higher in females than males. In thymus, one of the target organs of everolimus, concentrations were significantly higher at ZT1 than ZT13 and males compared to females (p<0.05). In mice treated with everolimus/vehicle for 14 days, liver P-gp expression was found higher at ZT13 than ZT1, and P-glycoprotein was slightly increased in each group upon everolimus administration. In controls, ileum P-gp expression was higher at ZT13 than ZT1, was affected by everolimus in both sexes differently. Our findings indicate that everolimus pharmacokinetics may vary according to dosing-time, sex, and feeding in mice. Higher everolimus tissue distribution at ZT1 may explain the cause of everolimus chronotoxicity. Our study support that everolimus can be more effective and safer with chronotherapeutical approach.