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

• Published in: Scientific reports 2019-07, Vol.9 (1), p.10505-15, Article 10505
• Main Authors: Okyar, Alper, Kumar, Swati A., Filipski, Elisabeth, Piccolo, Enza, Ozturk, Narin, Xandri-Monje, Helena, Pala, Zeliha, Abraham, Kristin, Gomes, Ana Rita Gato de Jesus, Orman, Mehmet N., Li, Xiao-Mei, Dallmann, Robert, Lévi, Francis, Ballesta, Annabelle
• Format: Article
• Language: English
• Subjects: 59; 59/5; 631/553/2700; 64; 64/110; 64/60; 692/308/575; 692/4017; 692/700/565/1436/152; 692/700/565/1436/99; 82; 82/16; 82/51; 82/80; Animals; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP Binding Cassette Transporter, Subfamily B - metabolism; Biological Transport; Bioluminescence; Circadian Rhythm; Circadian rhythms; Citalopram - pharmacokinetics; Colon - metabolism; Crosses, Genetic; Eating - physiology; Fasting - physiology; Feeding; Female; Females; Gene Expression Regulation; Glycoproteins; Humanities and Social Sciences; Ileum; Ileum - metabolism; Intestinal Mucosa - metabolism; Liver; Liver - metabolism; Male; Males; Mice; Mice, Inbred C57BL; Models, Biological; mRNA; multidisciplinary; P-Glycoprotein; Pharmacokinetics; Pharmacology; Propanolamines - analysis; Propanolamines - pharmacokinetics; Rhythm; RNA, Messenger - biosynthesis; Science; Science (multidisciplinary); Sex; Sex Characteristics; Transgenic mice; Xenobiotics
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-46977-0

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.