Dosing-time, feeding, and sex-dependent variations of everolimus pharmacokinetics in mice

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dc.authoridOzturk Civelek, Dilek/0000-0003-2485-891X
dc.contributor.authorOzturk Civelek, Dilek
dc.contributor.authorOzturk Seyhan, Narin
dc.contributor.authorAkyel, Yasemin Kubra
dc.contributor.authorGazioglu, Isil
dc.contributor.authorPala Kara, Zeliha
dc.contributor.authorOrman, Mehmet N.
dc.contributor.authorOkyar, Alper
dc.date.accessioned2024-08-31T07:47:45Z
dc.date.available2024-08-31T07:47:45Z
dc.date.issued2024
dc.departmentEge Üniversitesien_US
dc.description.abstractBackgroundEverolimus is an oral mammalian target of rapamycin (mTOR) inhibitor used as an immunosuppressant and anticancer. 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.ObjectivesIn 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.MethodA 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 24 h following drug administration. Ileum, liver, plasma, and thymus concentrations of everolimus were determined.ResultsFemales had a greater ileum AUC0-24h than males when fed (P = 0.043). Everolimus AUC0-24h in the liver was substantially greater at ZT1 than at ZT13 in a fasted state (P = 0.001). Plasma Cmax, AUC0-24h, and AUCtotal were not statistically significant between the groups (P = 0.098). In one of the target organs of everolimus, the thymus, males had considerably higher amounts at ZT1 than females (P = 0.029).ConclusionOur 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.en_US
dc.description.sponsorshipResearch Fund of Istanbul Universityen_US
dc.description.sponsorshipThe authors thank Ferdi Ozturk, Pharm. MSc. for his assistance on the animal studies, Semiha Ozgul, MSc. for her assistance on statistical analysis, and Prof. Durisehvar Unal, Ph.D. for the donation of internal standard repaglinide.en_US
dc.identifier.doi10.1111/fcp.13003
dc.identifier.issn0767-3981
dc.identifier.issn1472-8206
dc.identifier.pmid38500383en_US
dc.identifier.scopus2-s2.0-85188539737en_US
dc.identifier.scopusqualityQ2en_US
dc.identifier.urihttps://doi.org/10.1111/fcp.13003
dc.identifier.urihttps://hdl.handle.net/11454/104515
dc.identifier.wosWOS:001187046700001en_US
dc.identifier.wosqualityN/Aen_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherWileyen_US
dc.relation.ispartofFundamental & Clinical Pharmacologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.snmz20240831_Uen_US
dc.subjectChronomodulated Chemotherapyen_US
dc.subjectChronopharmacokineticsen_US
dc.subjectEverolimusen_US
dc.subjectFed/Fasteden_US
dc.subjectSex Differenceen_US
dc.titleDosing-time, feeding, and sex-dependent variations of everolimus pharmacokinetics in miceen_US
dc.typeArticleen_US

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