In vitro models for the blood–brain barrier

The aim of the present study was to identify a model for the blood–brain barrier based on the use of a continuous cell line, and to investigate the specificity of this model. A set of test compounds, reflecting different transport mechanisms and different degrees of permeability, as well as differen...

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Veröffentlicht in:Toxicology in vitro 2005-04, Vol.19 (3), p.299-334
Hauptverfasser: Garberg, P., Ball, M., Borg, N., Cecchelli, R., Fenart, L., Hurst, R.D., Lindmark, T., Mabondzo, A., Nilsson, J.E., Raub, T.J., Stanimirovic, D., Terasaki, T., Öberg, J.-O., Österberg, T.
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Sprache:eng
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Zusammenfassung:The aim of the present study was to identify a model for the blood–brain barrier based on the use of a continuous cell line, and to investigate the specificity of this model. A set of test compounds, reflecting different transport mechanisms and different degrees of permeability, as well as different physiochemical properties was selected. In vivo data for transport across the blood–brain barrier of this set of test compounds was generated as part of the study using two different in vivo models. A computational prediction model was also developed, based on 74 proprietary Pharmacia compounds, previously tested in one of the in vivo models. Molsurf descriptors were calculated and 21 descriptors were correlated with log(Brain conc./Plasma conc.) using partial least squares projection to latent structures (PLS). However, the correlation between predicted and measured values was found to be rather low and differed between one and two log units for several of the compounds. The test compounds were analyzed in vitro using primary bovine and human brain endothelial cells co-cultured with astrocytes, and also using two different immortalized brain endothelial cell lines, one originating from rat and one from mouse. Cell models using cells not derived from the blood–brain barrier, ECV/C6, MDCK and Caco-2 cell lines, were also used. No linear correlation between in vivo and in vitro permeability was found for any of the in vitro models when all compounds were included in the analysis. The highest r 2 values were seen in the bovine brain endothelial cells ( r 2 = 0.43) and MDCKwt ( r 2 = 0.46) cell models. Higher correlations were seen when only passively transported compounds were included in the analysis, bovine brain endothelial cells ( r 2 = 0.74), MDCKwt ( r 2 = 0.65) and Caco-2 ( r 2 = 0.86). By plotting in vivo P app values against log D pH 7.4 it was possible to classify compounds into four different classes: (1) compounds crossing the blood–brain barrier by passive diffusion, (2) compounds crossing the blood–brain barrier by blood-flow limited passive diffusion, (3) compounds crossing the blood–brain barrier by carrier mediated influx, and (4) compounds being actively excreted from the brain by active efflux. P app and P e values obtained using the different in vitro models were also plotted against log D pH 7.4 and compared to the plot obtained when in vivo P app values were used. Several of the in vitro models could distinguish between passively distributed
ISSN:0887-2333
1879-3177
DOI:10.1016/j.tiv.2004.06.011