Comparison of brain capillary endothelial cell-based and epithelial (MDCK-MDR1, Caco-2, and VB-Caco-2) cell-based surrogate blood–brain barrier penetration models

• Published in: European journal of pharmaceutics and biopharmaceutics Vol. 82; no. 2; pp. 340 - 351
• Main Authors: Hellinger, Éva, Veszelka, Szilvia, Tóth, Andrea E., Walter, Fruzsina, Kittel, Ágnes, Bakk, Mónika Laura, Tihanyi, Károly, Háda, Viktor, Nakagawa, Shinsuke, Dinh Ha Duy, Thuy, Niwa, Masami, Deli, Mária A., Vastag, Monika
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.10.2012; Elsevier
• Subjects: Animals; Astrocytes - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Biological Transport; Blood-Brain Barrier - metabolism; Blood–brain barrier; Brain - cytology; Brain - metabolism; Brain endothelial cell; Caco-2 Cells; Cell Line; Coculture Techniques; Endothelial Cells - metabolism; General pharmacology; Humans; Madin Darby Canine Kidney Cells; MDCK-MDR1; Medical sciences; Mice; Mice, Inbred BALB C; P-glycoprotein; Pericytes - metabolism; Permeability; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Rats; Rats, Wistar; Surrogate BBB model; VB-Caco-2; P-glycoprotein; MDCK-MDR1; Brain endothelial cell; VB-Caco-2; Blood–brain barrier; Surrogate BBB model; Endothelial cell; Pharmaceutical technology; P Glycoprotein; Gut; Blood brain barrier; Encephalon; Penetration; Blood-brain barrier; MDR-1 gene; Pharmacokinetics; Comparative study
• ISSN: 0939-6411; 1873-3441
• DOI: 10.1016/j.ejpb.2012.07.020

Functional and morphological comparison of the primary endothelial triple co-culture blood–brain barrier (BBB) model, the high P-glycoprotein expressing vinblastine-treated Caco-2 (VB-Caco-2), and the MDCK-MDR1 surrogate BBB model. An accurate means of predicting blood–brain barrier (BBB) penetration and blood–brain partitioning of NCEs (new chemical entities) would fulfill a major need in pharmaceutical research. Currently, an industry-standard BBB drug penetration model is not available. Primary brain capillary endothelial cells, optionally co-cultured with astrocytes and/or pericytes, are the most valued models of BBB. For routine use, establishing and maintaining a co-culture system is too costly and labor intensive. Alternatively, non-cerebral cell lines such as MDCK-MDR1 are used, and most recently, the suitability of native and modified Caco-2 for predicting brain penetration has also come under investigation. This study provides comparative data on the morphology and functionality of the high integrity brain capillary endothelial BBB model (EPA: triple culture of brain capillary endothelial cells with pericytes and astrocytes) and the epithelial cell-based (native Caco-2, high P-glycoprotein expressing vinblastine-treated VB-Caco-2 and MDCK-MDR1) surrogate BBB models. Using a panel of 10 compounds VB-Caco-2 and MDCK-MDR1 cell lines show restrictive paracellular pathway and BBB-like selective passive permeability that makes them comparable to the rat brain BBB model, which gave correlation with the highest r2 value with in vivo permeability data. In bidirectional assay, the VB-Caco-2 and the MDCK-MDR1 models identified more P-glycoprotein drug substrates than the rat brain BBB model. While the complexity and predictive value of the BBB model is the highest, for the screening of NCEs to determine whether they are efflux substrates or not, the VB-Caco-2 and the MDCK-MDR1 models may provide a simple and inexpensive tool.