P-glycoprotein protein expression versus functionality at the blood-brain barrier using immunohistochemistry, microdialysis and mathematical modeling

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences
Elizabeth C M de LangeStina Syvänen

Abstract

A proper understanding of P-gp mediated transport (functionality) at the blood-brain barrier (BBB) and beyond is needed to interpret, understand and predict pharmacokinetic (PK)- pharmacodynamic (PD) relationships of CNS drugs that are substrates of P-gp, especially since P-gp functionality may be different in different conditions. Often, P-gp expression is taken as a biomarker of transporter functionality. The aim of our study was to investigate whether brain capillary protein expression of P-gp is associated with changes in P-gp mediated drug efflux at the BBB. Status Epilepticus (SE) was induced by kainate in male rats. During 3-5 weeks post SE, hippocampal P-gp expression was determined using immunohistochemistry, while BBB P-gp functionality was assessed by microdialysis of quinidine, in absence and presence of the P-gp blocker tariquidar. The data were analyzed using Non-linear Mixed Effect Modeling implemented in NONMEM. Following SE, changes in brain capillary P-gp expression were observed. However, no relation between BBB P-gp protein expression and BBB P-gp mediated drug efflux was found. This warrants a critical view on the interpretation of reported changes in BBB P-gp expression as a biomarker of BBB P-gp functiona...Continue Reading

Citations

May 30, 2019·The AAPS Journal·Jean-Marie Nicolas, Elizabeth C M de Lange
Dec 7, 2018·Frontiers in Aging Neuroscience·Feixue WangHao Li
Jun 15, 2019·Micromachines·Lili JiangHui Huang
Dec 24, 2019·Acta Pharmaceutica Sinica. B·Yuhua LiHuichang Bi
Dec 17, 2020·Frontiers in Neurology·Quirijn P VerhoogErwin A van Vliet
Jan 31, 2021·Computer Methods and Programs in Biomedicine·Zeyu WuWencheng Zhang
Feb 25, 2021·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Yu Jiao-YanYang Qi
Dec 31, 2020·Journal of Chemical Information and Modeling·Rong YangRuizhi Zhao

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