PMID- 38500383
OWN - NLM
STAT- Publisher
LR  - 20240319
IS  - 1472-8206 (Electronic)
IS  - 0767-3981 (Linking)
DP  - 2024 Mar 18
TI  - Dosing-time, feeding, and sex-dependent variations of everolimus pharmacokinetics 
      in mice.
LID - 10.1111/fcp.13003 [doi]
AB  - BACKGROUND: Everolimus 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. OBJECTIVES: 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. METHOD: 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 24 h following drug administration. Ileum, liver, plasma, 
      and thymus concentrations of everolimus were determined. RESULTS: Females had a 
      greater ileum AUC(0-24h) than males when fed (P = 0.043). Everolimus AUC(0-24h) 
      in the liver was substantially greater at ZT1 than at ZT13 in a fasted state 
      (P = 0.001). Plasma C(max) , AUC(0-24h) , and AUC(total) 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). CONCLUSION: 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.
CI  - (c) 2024 Societe Francaise de Pharmacologie et de Therapeutique. Published by John 
      Wiley & Sons Ltd.
FAU - Ozturk Civelek, Dilek
AU  - Ozturk Civelek D
AUID- ORCID: 0000-0003-2485-891X
AD  - Department of Pharmacology, Faculty of Pharmacy, Bezmialem Vakif University, 
      Istanbul, Turkey.
AD  - Department of Pharmacology, Faculty of Pharmacy, Istanbul University, Istanbul, 
      Turkey.
FAU - Ozturk Seyhan, Narin
AU  - Ozturk Seyhan N
AD  - Department of Pharmacology, Faculty of Pharmacy, Istanbul University, Istanbul, 
      Turkey.
FAU - Akyel, Yasemin Kubra
AU  - Akyel YK
AD  - Department of Medical Pharmacology, School of Medicine, Istanbul Medipol 
      University, Istanbul, Turkey.
FAU - Gazioglu, Isil
AU  - Gazioglu I
AD  - Department of Analytical Chemistry, Faculty of Pharmacy, Bezmialem Vakif 
      University, Istanbul, Turkey.
AD  - Applied Analytical Chemistry, Faculty of Chemistry, University of Duisburg-Essen, 
      Essen, Germany.
FAU - Pala Kara, Zeliha
AU  - Pala Kara Z
AD  - Department of Pharmacology, Faculty of Pharmacy, Istanbul University, Istanbul, 
      Turkey.
FAU - Orman, Mehmet N
AU  - Orman MN
AD  - Department of Biostatistics and Medical Informatics, Faculty of Medicine, Ege 
      University, Bornova, Izmir, Turkey.
FAU - Okyar, Alper
AU  - Okyar A
AD  - Department of Pharmacology, Faculty of Pharmacy, Istanbul University, Istanbul, 
      Turkey.
LA  - eng
GR  - YOP-24831/Research Fund of Istanbul University/
GR  - 216S475/Scientific and Technological Research Council of Turkey-TUBITAK/
PT  - Journal Article
DEP - 20240318
PL  - England
TA  - Fundam Clin Pharmacol
JT  - Fundamental & clinical pharmacology
JID - 8710411
SB  - IM
OTO - NOTNLM
OT  - chronomodulated chemotherapy
OT  - chronopharmacokinetics
OT  - everolimus
OT  - fed/fasted
OT  - sex difference
EDAT- 2024/03/19 06:43
MHDA- 2024/03/19 06:43
CRDT- 2024/03/19 02:53
PHST- 2024/01/01 00:00 [revised]
PHST- 2023/05/11 00:00 [received]
PHST- 2024/02/19 00:00 [accepted]
PHST- 2024/03/19 06:43 [medline]
PHST- 2024/03/19 06:43 [pubmed]
PHST- 2024/03/19 02:53 [entrez]
AID - 10.1111/fcp.13003 [doi]
PST - aheadofprint
SO  - Fundam Clin Pharmacol. 2024 Mar 18. doi: 10.1111/fcp.13003.