Leakiness and Size Exclusion of Paracellular Channels in Cultured Epithelial Cell Monolayers–Interlaboratory Comparison

Abstract

To determine and compare the paracellular characteristics of permeability (Papp) of Caco-2, MDCK, and 2/4/A1 cell lines. The Papp data from 14 studies were analyzed by weighted nonlinear regression in terms of the paracellular parameters: porosity-pathlength (ε/δ), pore radius (R), and electrostatic potential drop (Δφ). Aqueous diffusivities, Daq, for the analysis, were empirically determined. The required hydrodynamic radii, rHYD, were estimated without knowledge of compound density. Mannitol iso-paracellular profiles allowed comparisons of “leakiness” across labs. Daq (37°C) was predicted as 9.9 × 10−5 MW−0.453; rHYD = (0.92 + 21.8 MW−1)·rSE, where rSE is the Stokes-Einstein radius. Values of pore radius ranged from 4.0(±0.1) to 18(±3) Å, with the 2/4/A1 indicating the largest pores. The ε/δ capacity factor ranged from 0.2 (±0.1) to 69 (±5) cm−1, with most values <1.5 cm−1. The average potential drop for Caco-2 models was Δφ wt avg Caco-2  = −43 ± 20 mV. The paracellular model predicted measured log Papp values with pooled r 2 = 0.93 and s = 0.17 (n = 108). R and ε/δ are negatively correlated to a large extent. Papp can be rate-limited by either factor, with a wide range of possible combinations still indicating nearly constant leakiness for a given marker.

DOI: 10.1007/s11095-009-0036-7

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@article{Avdeef2009LeakinessAS, title={Leakiness and Size Exclusion of Paracellular Channels in Cultured Epithelial Cell Monolayers–Interlaboratory Comparison}, author={Alex Avdeef}, journal={Pharmaceutical Research}, year={2009}, volume={27}, pages={480-489} }