Cyclosporine A kinetics in brain cell cultures and its potential of crossing the blood-brain barrier.

Details

Serval ID
serval:BIB_7942021B330D
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Cyclosporine A kinetics in brain cell cultures and its potential of crossing the blood-brain barrier.
Journal
Toxicology In Vitro : An International Journal Published In Association With Bibra
Author(s)
Bellwon P., Culot M., Wilmes A., Schmidt T., Zurich M.G. (co-first), Schultz L., Schmal O., Gramowski-Voss A., Weiss D.G., Jennings P., Bal-Price A., Testai E., Dekant W.
ISSN
1879-3177 (Electronic)
ISSN-L
0887-2333
Publication state
Published
Issued date
2015
Peer-reviewed
Oui
Volume
30
Number
1 Pt A
Pages
166-175
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
There is an increasing need to develop improved systems for predicting the safety of xenobiotics. However, to move beyond hazard identification the available concentration of the test compounds needs to be incorporated. In this study cyclosporine A (CsA) was used as a model compound to assess the kinetic profiles in two rodent brain cell cultures after single and repeated exposures. CsA induced-cyclophilin B (Cyp-B) secretion was also determined as CsA-specific pharmacodynamic endpoint. Since CsA is a potent p-glycoprotein substrate, the ability of this compound to cross the blood-brain barrier (BBB) was also investigated using an in vitro bovine model with repeated exposures up to 14 days. Finally, CsA uptake mechanisms were studied using a parallel artificial membrane assay (PAMPA) in combination with a Caco-2 model. Kinetic results indicate a low intracellular CsA uptake, with no marked bioaccumulation or biotransformation. In addition, only low CsA amounts crossed the BBB. PAMPA and Caco-2 experiments revealed that CsA is mostly trapped to lipophilic compartments and exits the cell apically via active transport. Thus, although CsA is unlikely to enter the brain at cytotoxic concentrations, it may cause alterations in electrical activity and is likely to increase the CNS concentration of other compounds by occupying the BBBs extrusion capacity. Such an integrated testing system, incorporating BBB, brain culture models and kinetics could be applied for assessing neurotoxicity potential of compounds.
Keywords
Animals, Blood-Brain Barrier/physiology, Brain/cytology, Caco-2 Cells, Cell Culture Techniques, Cells, Cultured, Cyclosporine/pharmacokinetics, Embryo, Mammalian/cytology, Humans, Mice, Neurons/drug effects, Rats, Rats, Sprague-Dawley
Pubmed
Web of science
Create date
02/02/2016 17:47
Last modification date
17/01/2020 6:18
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