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Drug Metabolism and Disposition Fast Forward
First published on August 8, 2006; DOI: 10.1124/dmd.105.006437

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Received for publication July 14, 2005.
Revised August 2, 2006.
Accepted for publication August 3, 2006.

Porcine Brain Microvessel Endothelial Cells (PBMEC) as an In Vitro Model to Predict In Vivo Blood-Brain Barrier (BBB) Permeability

Yan Zhang 1, Cheryl S. W. Li 2*, Yuyang Ye 2, Kjell Johnson 2, Julie Poe 2, Shannon Johnson 2, Walter Bobrowski 2, Rosario Garrido 2, Cherukury Madhu 3

1 Incyte Corporation 2 Pfizer Inc. 3 Abbott Bioresearch Center

* Address correspondence to: E-mail: cheryl.li{at}pfizer.com

Abstract

The objective of the study was to establish primary cultured porcine brain microvessel endothelial cells (PBMEC) as an in vitro model to predict the blood-brain barrier (BBB) permeability in vivo. The intercellular tight junction formation of PBMEC was examined by electron microscopy and measured by Transendothelial Electrical Resistance (TEER). The mRNA expression of several BBB transporters in PBMEC was determined by RT-PCR analysis. The in vitro permeability of 16 structurally diverse compounds, representing a range of passive diffusion and transporter-mediated mechanisms of brain penetration, was determined in PBMEC. Except for the perfusion flow rate marker diazepam, the BBB permeability of these compounds was determined either in our laboratory or reported in literature using in situ brain perfusion technique in rats. Results in the present study showed that PBMEC had a high endothelium homogeneity, an mRNA expression of several BBB transporters, and high TEER values. Culturing with rat astrocyte-conditioned medium increased the TEER of PBMEC, but had no effect on the permeability of sucrose, a paracellular diffusion marker. The PBMEC permeability of lipophilic compounds measured under stirred conditions was greatly increased compared to measured under unstirred conditions. The PBMEC permeability of the 15 test compounds, determined under the optimized study conditions, correlated with the in situ BBB permeability with an r2 of 0.60. Removal of the three system L substrates increased the r2 to 0.89. In conclusion, the present PBMEC model may be used to predict or rank the in vivo BBB permeability of new chemical entities (NCEs) in a drug discovery setting.


Key words: blood-brain barrier, drug distribution, in vitro-in vivo prediction, permeability


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J. Pharmacol. Exp. Ther., May 1, 2008; 325(2): 349 - 356.
[Abstract] [Full Text] [PDF]


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