Physicochemical QSAR Analysis of Passive Permeability Across Caco-2 Monolayers

Abstract

Caco-2 cell line is frequently used as a simplified in vitro model of intestinal absorption. In this study, a database of 1366 Caco-2 permeability coefficients (Pe) for 768 diverse drugs and drug-like compounds was compiled from public sources. The collected data represent permeation rates measured at varying experimental conditions (pH from 4.0 to 8.0, and stirring rates from 0 to >1000 rpm) that presumably account for passive diffusion across mucosal epithelium. These data were subjected to multistep nonlinear regression analysis using a minimal set of physicochemical descriptors (octanol-water log D, pKa, hydrogen bonding potential, and molecular size). The model was constructed in a mechanistic manner incorporating the following components: (i) a hydrodynamic equation of size- and charge-specific along with nonspecific diffusion across the paracellular pathway; (ii) transcellular diffusion represented by thermodynamic membrane/water partitioning ratio; (iii) stirring-dependent limit of maximum achievable permeability due to the presence of unstirred water layer. The obtained model demonstrates good accuracy of log Pe predictions with a residual mean square error <0.5 log units for all training and validation sets. Given its robust performance and straightforward interpretation in terms of simple physicochemical properties, the proposed model may serve as a valuable tool to guide drug discovery efforts toward readily absorbable compounds.