Marked Differences in the Effect of Antiepileptic and Cytostatic Drugs on the Functionality of P-Glycoprotein in Human and Rat Brain ... View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2014-01-30

AUTHORS

Dana Alms, Maren Fedrowitz, Kerstin Römermann, Andreas Noack, Wolfgang Löscher

ABSTRACT

ABSTRACTPurposeThe expression of P-glycoprotein (Pgp) is increased in brain capillary endothelial cells (BCECs) of patients with pharmacoresistant epilepsy. This may restrict the penetration of antiepileptic drugs (AEDs) into the brain. However, the mechanisms underlying increased Pgp expression in epilepsy patients are not known. One possibility is that AEDs induce the expression and functionality of Pgp in BCECs. Several older AEDs that induce human cytochrome P450 enzymes also induce Pgp in hepatocytes and enterocytes, but whether this extends to Pgp at the human BBB and to newer AEDs is not known.MethodsThis prompted us to study the effects of various old and new AEDs on Pgp functionality in the human BCEC line, hCMEC/D3, using the rhodamine 123 (Rho123) efflux assay. For comparison, experiments were performed in two rat BCEC lines, RBE4 and GPNT, and primary cultures of rat and pig BCECs. Furthermore, known Pgp inducers, such as dexamethasone and several cytostatic drugs, were included in our experiments.ResultsUnder control conditions, GPNT cells exhibited the highest and RBE4 the lowest Pgp expression and Rho123 efflux, while intermediate values were determined in hCMEC/D3. Known Pgp inducers increased Rho123 efflux in all cell lines, but marked inter-cell line differences in effect size were observed. Of the various AEDs examined, only carbamazepine (100 μM) moderately increased Pgp functionality in hCMEC/D3, while valproate (300 μM) inhibited Pgp.ConclusionsThese data do not indicate that treatment with AEDs causes a clinically relevant induction in Pgp functionality in BCECs that form the BBB. More... »

PAGES

1588-1604

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s11095-013-1264-4

DOI

http://dx.doi.org/10.1007/s11095-013-1264-4

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1046584146

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/24477677


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