Application of a bioengineered intestinal epithelium for drug permeability and metabolism studies

The small intestine is the most important site of absorption for many orally administered drugs. Following absorption, intestinal and hepatic first-pass metabolism reduce the amount of drug that reaches the systemic circulation and hence the intended therapeutic target. In vitro models can be used to predict intestinal permeability and metabolism, enabling optimization of drug candidate properties for improved oral bioavailability. Currently, data from separate metabolism and permeability assays is combined using modelling approaches, but this does not allow for assessment of interconnected processes. An in vitro system which captures both intestinal permeability and metabolism could improve human pharmacokinetics (PK) prediction accuracy. In this study, a human organoid based bioengineered intestinal epithelium (BIE) with apical and basolateral partitioning and crypt-axis patterning was characterized with regards to barrier function as well as the presence of key drug-metabolizing enzymes (DMEs) and drug transporters (DTs). Drug transport studies validated the function of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) through targeted inhibition. Furthermore, the BIE's capability to estimate drug metabolic parameters is demonstrated through mathematical mechanistic modeling to predict the fraction escaping gut metabolism (F_g). Results indicate consistent tissue patterning and the potential to assess drug permeability and metabolism in the gut simultaneously. The use of intestinal organoids in a microphysiological system coupled with in silico modeling holds significant promise to innovate oral drug bioavailability assessment and aid in drug formulation and safety screening.