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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
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Official URL: https://doi.org/10.1038/s41598-019-46977-0
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 | ||||||||||||||||||||||||
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| Subjects: | Q Science > QH Natural history Q Science > QP Physiology R Medicine > RM Therapeutics. Pharmacology |
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| Divisions: | Faculty of Medicine > Warwick Medical School > Biomedical Sciences Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine Faculty of Medicine > Warwick Medical School |
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| 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 | ||||||||||||||||||||||||
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| 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 | ||||||||||||||||||||||||
| RIOXX Funder/Project Grant: |
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