Systematic evaluation of permeability-related behavior and physicochemical determinants of structurally diverse phytochemicals using a Caco-2 cell model

Abstract

Understanding the intestinal permeability of phytochemicals is essential for elucidating their bioavailability and physiological efficacy. This study systematically investigated 162 structurally diverse phytochemicals across 15 chemical classes using the human intestinal Caco-2 cell monolayer model. Transepithelial electrical resistance (TEER), apparent permeability coefficients (P_app), and efflux ratios (ER) were determined to evaluate barrier integrity, passive diffusion, and transporter-mediated efflux, respectively. TEER responses ranged from 44.4 ± 0.5% to 138.8 ± 10.2% across the 162 compounds, indicating both barrier-disruptive and barrier-enhancing effects depending on compound structure. Apparent permeability coefficients (P_app, AP → BL) spanned 0.11 ± 0.13 × 10⁻⁶ to 129.0 ± 6.6 × 10⁻⁶ cm s⁻¹, demonstrating large variability across classes. Among these, alkaloids, benzopyrans, flavonoids, and phenolic compounds exhibited the highest permeability, whereas ginsenosides, polysaccharides, and polypeptides were largely undetectable. P_app and recovery values correlated positively with lipophilicity (X log P) but negatively with topological polar surface area (TPSA) and hydrogen bonding capacity (HBD, HBA). Principal component analysis (PCA) integrating physicochemical and permeability-related variables explained 63.8% of total variance and illustrated overall multivariate associations among variables. PCA was used as an exploratory visualization tool and suggested that permeability-related parameters were associated with lipophilicity and molecular polarity rather than chemical class alone. These observations provide descriptive insight into structure–permeability relationships but should be interpreted in conjunction with direct permeability measurements.