How well can in vitro brain microcapillary endothelial cell models predict rodent in vivo blood-brain barrier permeability?

The object of the study was to improve the blood-brain barrier (BBB) permeability in vitro-in vivo correlations (IVIVC) between in vitro brain microcapillary endothelial cell (BMEC) models and the well-tested rodent in situ brain perfusion technique. Porcine, bovine, rat, mouse, and human in vitro BMEC apparent permeability values, P-e, (14 studies from several laboratories: 229 P-e, 60 compounds) were analyzed by a novel biophysical model encoded in a weighted nonlinear regression procedure to determine the aqueous boundary layer (ABL) thickness and the paracellular parameters: porosity-pathlength (dual-pore model), pore radius, and water channel electrostatic potential. The refined parameters were then used to transform the P-e values into the transendothelial permeability (P-c) values. Porcine BMEC mono-culture models showed tight junctions comparable to those reported in several Caco-2 studies. Bovine cultures were somewhat leakier. In the human primary cultured cell and the hCMEC/D3 cell line data, IVIVC based on P-e values has r(2) = 0.14. With transformed permeability values, r(2) = 0.58. Comparable improvements were found in the other species data. By using the in vitro transendothelial P-c values in place of the apparent P-e values, IVIVC can be dramatically improved. (C) 2011 Elsevier B.V. All rights reserved,