Uptake and Transport of Monotropein and Monotropein Esters in a Caco‐2/HT29‐MTX‐E12 Co‐Culture Model

ABSTRACT Iridoids are dietary phytochemicals with diverse bioactivities, but their intestinal absorption remains poorly understood. We investigated the uptake, transepithelial transport, and early metabolism of monotropein and two esters (monotropein‐10‐coumarate and monotropein‐10‐cinnamate) using a validated Caco‐2:HT29‐MTX‐E12 co‐culture model. In silico analysis showed high polarity (>186 Å 2 ) and predominant ionization at intestinal pH (p K a ∼ 4.10–4.14), consistent with low passive permeability. Cellular uptake was rapid and largely time‐independent. Monotropein uptake increased at 4°C versus 37°C, suggesting reduced efflux or metabolism rather than active transport; esters were unaffected. Transepithelial transport was low but increased at apical pH 6.0 compared to pH 7.4. Parallel artificial membrane assays (PAMPA) confirmed low passive permeability. Transporter inhibition indicated partial involvement of sodium–glucose cotransporter 1 (SGLT1) and organic anion transporting polypeptides (OATP) in monotropein uptake. Untargeted HPLC‐MS detected no metabolites, and esters were not hydrolyzed. Overall, permeability was limited and not improved by esterification, suggesting low systemic exposure and a potential role for colonic and hepatic metabolism in vivo.