Abstract
Induction of intestinal drug metabolizing enzymes can complicate the development of new drugs, owing to the potential to cause drug-drug interactions (DDIs) leading to changes in pharmacokinetics, safety and efficacy. The development of a human-relevant model of the adult intestine that accurately predicts CYP450 induction could help address this challenge as species differences preclude extrapolation from animals. Here, we combined organoids and Organs-on-Chips technology to create a human Duodenum Intestine-Chip that emulates intestinal tissue architecture and functions, that are relevant for the study of drug transport, metabolism, and DDI. Duodenum Intestine-Chip demonstrates the polarized cell architecture, intestinal barrier function, presence of specialized cell subpopulations, and in vivo relevant expression, localization, and function of major intestinal drug transporters. Notably, in comparison to Caco-2, it displays improved CYP3A4 expression and induction capability. This model could enable improved in vitro to in vivo extrapolation for better predictions of human pharmacokinetics and risk of DDIs.
Highlights
Low bioavailability and pharmacokinetics caused by drug-drug interactions of orally administered drugs represents a significant challenge in the modern drug development
We first established organoid cultures (Figure 1A; top) from crypts isolated from endoscopic biopsies of three different healthy adult individuals, the organoids were dissociated into fragments and seeded on the top of the Extracellular Matrix (ECM)-coated porous flexible polydimethylsiloxane (PDMS) membrane of the chips (Figure 1B; 3: indicates the epithelial tissue)
There is a need for new models for predicting human ADME and determining risk for drug-drug interactions (DDIs) mediated by intestinal CYP450s and drug transporters
Summary
Low bioavailability and pharmacokinetics caused by drug-drug interactions of orally administered drugs represents a significant challenge in the modern drug development. The hepatic drug clearance is well-understood and relatively well predicted by pre-clinical models, while the accurate prediction of the first-pass extraction of xenobiotics in human intestinal epithelium still remains elusive. This is due to a number of confounding factors that affect oral drug absorption including the properties of the compound (solubility, permeability), physiology of the intestinal tract (transit time, blood flow), and patient phenotype (including age, gender, polymorphism in drug metabolizing enzymes, disease states) (Pang, 2003).
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