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Its pharmacokinetics is highly variable, it has a narrow therapeutic window and shows chronotoxicity with the best time at ZT13 and worst time at ZT1 (ZT; Zeitgeber time, time after light onset) in the preclinical setting.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>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 with the chronopharmacokinetics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>A single dosage of 5\u00a0mg\/kg everolimus was administered orally to C57BL\/6J male and female mice, in fed or fasted states at ZT1\u2010rest and ZT13\u2010activity times and blood and tissue samples were collected at 0.5, 1, 2, 4, 12, and 24\u2009h following drug administration. Ileum, liver, plasma, and thymus concentrations of everolimus were determined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Females had a greater ileum AUC<jats:sub>0\u201324h<\/jats:sub> than males when fed (<jats:italic>P<\/jats:italic>\u2009=\u20090.043). Everolimus AUC<jats:sub>0\u201324h<\/jats:sub> in the liver was substantially greater at ZT1 than at ZT13 in a fasted state (<jats:italic>P<\/jats:italic>\u2009=\u20090.001). Plasma C<jats:sub>max<\/jats:sub>, AUC<jats:sub>0\u201324h<\/jats:sub>, and AUC<jats:sub>total<\/jats:sub> were not statistically significant between the groups (<jats:italic>P<\/jats:italic>\u2009=\u20090.098). In one of the target organs of everolimus, the thymus, males had considerably higher amounts at ZT1 than females (<jats:italic>P<\/jats:italic>\u2009=\u20090.029).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings imply that the pharmacokinetics of everolimus in mice may differ according to dosing time, sex, and feeding. 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.<\/jats:p><\/jats:sec>","DOI":"10.1111\/fcp.13003","type":"journal-article","created":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T07:30:54Z","timestamp":1710833454000},"page":"883-896","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Dosing\u2010time, feeding, and sex\u2010dependent variations of everolimus pharmacokinetics in mice"],"prefix":"10.1111","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2485-891X","authenticated-orcid":false,"given":"Dilek","family":"Ozturk Civelek","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy Bezmialem Vakif University  Istanbul Turkey"},{"name":"Department of Pharmacology, Faculty of Pharmacy Istanbul University  Istanbul 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Pharmacology, Faculty of Pharmacy Istanbul University  Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehmet N.","family":"Orman","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Medical Informatics, Faculty of Medicine Ege University  Bornova Izmir Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alper","family":"Okyar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy Istanbul University  Istanbul 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