Transepithelial Transport of Caffeoylquinic Acids in Caco-2 Cells: Structure Dependence and Modulation by Dietary Flavonoids

Caffeoylquinic acids (CQAs) are polyphenolic compounds widely present in daily diets, but their bioactivities are limited by poor intestinal absorption, the mechanisms of which remain incompletely understood for various isomers. This study investigated the transepithelial transport of three mono-CQAs and three di-CQAs using Caco-2 monolayers. Concurrently, the potential of five dietary flavonoids to enhance intestinal absorption by modulating efflux transporters was evaluated. Results suggest that CQAs were mainly transported via passive paracellular diffusion. The apparent permeability coefficients (Papp) of mono-CQAs were (1.49 ± 0.22) × 10−6, (1.49 ± 0.25) × 10−6, and (2.15 ± 0.57) × 10−6 cm/s, which were significantly higher than those of di-CQAs. And the efflux of 5-CQA, 3,4-diCQA, and 3,5-diCQA was primarily mediated by P-gp. Among the five dietary flavonoids tested for their potential to inhibit this efflux, quercetin and kaempferol exhibited the most potent enhancing CQA uptake. They increased the Papp of 5-CQA from (2.15 ± 0.21) × 10−6 to (3.05 ± 0.08) × 10−6 cm/s and (2.57 ± 0.17) × 10−6 cm/s, respectively. Similar promoting trends were observed for 3,4-diCQA and 3,5-diCQAs. Molecular docking revealed that CQAs and these effective flavonoids share common binding residues within the P-gp pocket, providing a structural basis for the inhibition of efflux. These findings provide insights into the intestinal transport of structurally diverse CQAs and highlight the potential of dietary flavonoids to improve the oral bioavailability of CQAs.