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

Détails

ID Serval
serval:BIB_7942021B330D
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Cyclosporine A kinetics in brain cell cultures and its potential of crossing the blood-brain barrier.
Périodique
Toxicology In Vitro : An International Journal Published In Association With Bibra
Auteur(s)
Bellwon P., Culot M., Wilmes A., Schmidt T., Zurich M.G. (co-premier), 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
Statut éditorial
Publié
Date de publication
2015
Peer-reviewed
Oui
Volume
30
Numéro
1 Pt A
Pages
166-175
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
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.
Mots-clé
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
Création de la notice
02/02/2016 18:47
Dernière modification de la notice
17/01/2020 7:18
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