Establishing the Human Duodenum Chip as a Surrogate for Effective Human Permeability: In Vitro and In Silico Assessment.

Drug permeability across epithelial barriers is critical for predicting oral bioavailability and efficacy. Conventional models, including animals and simple cell cultures, lack intestinal complexity and translational value. Organoids and organ-on-a-chip technologies address these limitations, offering physiologically relevant, human-specific platforms for more accurate drug permeability assessment [1]. Intestinal organoids, derived from stem cells, reproduce key structural and functional features of the gut, including crypt-villus organization, transporter and enzyme expression, and absorptive and secretory functions. Organoids are grown inside of microfluidic chips under dynamic media flow that attempt to recapitulate one or more tissue-specific functions, thereby supporting epithelial maturation and enabling more predictive drug transport measurements. Permeability can be studied by introducing compounds at the apical surface and quantifying their translocation to the basolateral compartment using analytical techniques. Compared with animal models, these approaches yield data of greater human relevance while reducing ethical concerns [2]. Furthermore, they enable the evaluation of passive permeability, active transport, intestinal metabolism, and interactions with microbial products [3]. In this study, permeability was investigated for three model compounds with distinct properties: lisinopril (low permeability), metoprolol (moderate permeability), and fluconazole (high permeability). Experiments were conducted using the Emulate human duodenum-on-a-chip platform and benchmarked against the Ralph Russ Canine Kidney (RRCK) cell line. Apparent permeability (Papp) values were correlated with literature-reported effective permeability (Peff) using linear regression. This regression was implemented in Simcyp® Simulator and GastroPlus™ to predict systemic exposure, which was compared against observed plasma concentration-time profiles.