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Dosing-time, feeding, and sex-dependent variations of everolimus pharmacokinetics in mice.
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  • Dilek Ozturk Civelek,
  • Narin Ozturk Seyhan,
  • Y. Kubra Akyel,
  • Isil Gazioglu,
  • Zeliha Pala Kara,
  • Mehmet Orman,
  • Alper Okyar
Dilek Ozturk Civelek
Bezmialem Vakif University Faculty of Pharmacy
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Narin Ozturk Seyhan
Istanbul University
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Y. Kubra Akyel
Istanbul Medipol University
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Isil Gazioglu
Bezmialem Vakif University Faculty of Pharmacy
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Zeliha Pala Kara
Istanbul University
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Mehmet Orman
Ege University
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Alper Okyar
Istanbul University

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Abstract

Everolimus is an oral mTOR inhibitor used as an immunosuppressant and anticancer. Its pharmacokinetics is highly variable, it has a narrow therapeutic window, and shows chronotoxicity with best time at ZT13 and worst time at ZT1 in preclinical setting. In the present study, we aimed to investigate whether the pharmacokinetics of everolimus vary according to dosing time and whether sex and feeding status interfere the chronopharmacokinetics. A single dosage of 5 mg/kg everolimus was administered orally to C57BL/6J male and female mice, in fed or fasted states at ZT1-rest and ZT13-activity times and blood and tissue samples were collected at 0.5, 1, 2, 4, 12, and 24h following drug administration. Plasma, liver, ileum, and thymus concentrations of everolimus were determined. Plasma C max, AUC 0-24h, and AUC total were greater at ZT13 compared to ZT1 for both sexes in each feeding states, although the difference was not statistically significant (p=0.098). Everolimus AUC 0-24h in the liver was substantially greater at ZT1 than ZT13 in fasted state (p=0.001). Females had a greater Ileum AUC0-24h than males when fed (p=0.043). In one of the target organs of everolimus, the thymus, males had considerably higher amounts at ZT1 than females (p=0.029). Our findings imply that pharmacokinetics of everolimus in mice may differ according to dosing-time, sex, and feeding. A greater tissue distribution of everolimus at ZT1 may be associated with the worst tolerated time of everolimus. Our research suggests that oral chronomodulated everolimus therapy may be more effective and safer for cancer patients.