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

Abstract

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.