Abcb1a (P-glycoprotein) limits brain exposure of the anticancer drug candidate seliciclib in vivo in adult mice
| Autor: | Beáta Tóth, Franciska Erdő, Annamária Bui, Ildikó Nagy, Zoltan Timar, Peter Krajcsi, Éva D. Molnár, Rémi Magnan |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Microdialysis ATP Binding Cassette Transporter Subfamily B Swine Antineoplastic Agents Cyclosporins Dibenzocycloheptenes Pharmacology Cell Line Capillary Permeability 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine In vivo Roscovitine Animals Humans Seliciclib P-glycoprotein biology General Neuroscience Anticancer drug In vitro 030104 developmental biology HEK293 Cells chemistry Blood-Brain Barrier Purines Area Under Curve biology.protein Quinolines Substrate specificity Efflux 030217 neurology & neurosurgery Central Nervous System Agents |
| Zdroj: | Brain research bulletin. 132 |
| ISSN: | 1873-2747 |
| Popis: | Seliciclib displayed limited brain exposure in vivo in adult rats with mature blood-brain barrier (BBB). Selicilib was shown to be a specific substrate of human ABCB1 in vitro. To demonstrate that ABCB1/Abcb1 can limit brain exposure in vivo in mice we are showing that seliciclib is a substrate of mouse Abcb1a, the murine ABCB1 ortholog expressed in the BBB as LLC-PK-Abcb1a cells displayed an efflux ratio (ER) of 15.31±3.54 versus an ER of 1.44±0.10 in LLC-PK1-mock cells. Additionally, in the presence of LY335979, an ABCB1/Abcb1a specific inhibitor, the observed ER for seliciclib in the LLC-PK1-mMdr1a cells decreased to 1.05±0.25. To demonstrate in vivo relevance of seliciclib transport by Abcb1a mouse brain microdialysis experiments were carried out that showed that the AUCbrain/AUCblood ratio of 0.143 in anesthetized mice increased about two-fold to 0.279 in the presence of PSC833 another ABCB1/Abcb1a specific inhibitor. PSC833 also increased the brain exposure (AUCbrain) of seliciclib close to 2-fold (136 vs 242) in awake mice. In sum, Abcb1a significantly decreases seliciclib permeability in vitro and is partly responsible for limited brain exposure of seliciclib in vivo in mice. |
| Databáze: | OpenAIRE |
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