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P-glycoprotein prot...
P-glycoprotein protein expression versus functionality at the blood-brain barrier using immunohistochemistry, microdialysis and mathematical modeling
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- De Lange, E. C. M. (author)
- Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands
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- van der Berg, D. J. (author)
- Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands
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- Bellanti, F. (author)
- Certara Strateg Consulting, Oss, Netherlands
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- Voskuyl, R. A. (author)
- Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands;SEIN, Heernstede, Netherlands
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- Syvänen, Stina (author)
- Uppsala universitet,Geriatrik,Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands
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(creator_code:org_t)
- Elsevier BV, 2018
- 2018
- English.
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In: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 124, s. 61-70
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Keyword
- P-glycoprotein
- Protein expression
- Functionality
- Blood-brain barrie
- Microdialysis
- Kainate
- Quinidine
Publication and Content Type
- ref (subject category)
- art (subject category)
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