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Sex-, feeding-, and circadian time-dependency of P-glycoprotein expression and activity - implications for mechanistic pharmacokinetics modeling

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Okyar, Alper, Kumar, Swati, Filipski, Elisabeth, Piccolo, Enza, Ozturk, Narin, Xandri-Monje, Helena, Pala-Kara, Zeliha, Abraham, Kristin, Gato de Jesus Gomes, Ana Rita, Orman, Mehmet N., Li, Robert Xiao-Mei, Dallmann, Robert, Lévi, Francis A. and Ballesta, Annabelle (2019) Sex-, feeding-, and circadian time-dependency of P-glycoprotein expression and activity - implications for mechanistic pharmacokinetics modeling. Scientific Reports, 9 . 10505. doi:10.1038/s41598-019-46977-0 ISSN 2045-2322.

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Official URL: https://doi.org/10.1038/s41598-019-46977-0

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Abstract

P-glycoprotein (P-gp) largely influences the pharmacokinetics (PK) and toxicities of xenobiotics in a patient-specific manner so that personalized drug scheduling may lead to significant patient’s benefit. This systems pharmacology study investigated P-gp activity in mice according to organ, sex, feeding status, and circadian time. Sex-specific circadian changes were found in P-gp ileum mRNA and protein levels, circadian amplitudes being larger in females as compared to males. Plasma, ileum and liver concentrations of talinolol, a pure P-gp substrate, significantly differed according to sex, feeding and circadian timing. A physiologically-based PK model was designed to recapitulate these datasets. Estimated mesors (rhythm-adjusted mean) of ileum and hepatic P-gp activity were higher in males as compared to females. Circadian amplitudes were consistently higher in females and circadian maxima varied by up to 10 h with respect to sex. Fasting increased P-gp activity mesor and dampened its rhythm. Ex-vivo bioluminescence recordings of ileum mucosae from transgenic mice revealed endogenous circadian rhythms of P-gp protein expression with a shorter period, larger amplitude, and phase delay in females as compared to males. Importantly, this study provided model structure and parameter estimates to refine PK models of any P-gp substrate to account for sex, feeding and circadian rhythms.

Item Type: Journal Article
Subjects: Q Science > QH Natural history
Q Science > QP Physiology
R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH): P-glycoprotein, Pharmacokinetics, Circadian rhythms, Bioluminescence
Journal or Publication Title: Scientific Reports
Publisher: Nature Publishing Group
ISSN: 2045-2322
Official Date: 19 July 2019
Dates:
DateEvent
19 July 2019Available
3 July 2019Accepted
Volume: 9
Article Number: 10505
DOI: 10.1038/s41598-019-46977-0
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access (Creative Commons)
Date of first compliant deposit: 4 July 2019
Date of first compliant Open Access: 29 July 2019
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
CaSyM, Grant 305033Seventh Framework Programmehttp://dx.doi.org/10.13039/100011102
N-7762/2010 İstanbul Üniversitesihttp://viaf.org/viaf/137781900
TUA-3760/2016 İstanbul Üniversitesihttp://viaf.org/viaf/137781900
UDP- 4023 İstanbul Üniversitesihttp://viaf.org/viaf/137781900
UDP-33403 İstanbul Üniversitesihttp://viaf.org/viaf/137781900
UNSPECIFIEDAssociation pour la Recherche sur le Temps Biologique et la ChronothérapieUNSPECIFIED
RD15023University of Warwickhttp://dx.doi.org/10.13039/501100000741
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