期刊
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
卷 124, 期 -, 页码 61-70出版社
ELSEVIER
DOI: 10.1016/j.ejps.2018.08.022
关键词
P-glycoprotein; Protein expression; Functionality; Blood-brain barrie; Microdialysis; Kainate; Quinidine
资金
- Foundation Epilepsy Institutions the Netherlands (SEIN)
- EU 7th Framework Programme EURIPIDES [201380]
- PKPD modeling platform 2
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 functionally. 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 functionally was assessed by microdialysis of quinidine, in absence and presence of the P-gp blocker tariquidar. The data were analyzed using Nonlinear 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 functionally.
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