Overview

Traditional immortalized intestinal cell lines and suspension hepatocytes have absent or low levels of metabolic enzyme expression, and thus fail to predict first pass human metabolism and oral bioavailability.

Introduction

Efforts to improve the in vitro to in vivo translation of drug efficacy and safety data has led to the emergence of more human relevant microphysiological systems (MPS) that consist of multiple, fluidically linked organs1. Here we describe a new MPS that links the jejunum (RepliGut® planar - jejunum) and liver using the PhysioMimix® Multi-organ System, with both cell types being of primary human origin.

Methods

The gut-liver MPS is established using the PhysioMimix® Multi-organ System and Dualorgan plate • Liver microtissues are formed by seeding primary human hepatocytes (PHH) on a 3D collagen coated scaffold • For the intestinal barrier, jejunum crypt epithelial stem cells were expanded and differentiated on a biomimetic scaffold, in static conditions • 4 days post PHH seeding, RepliGut® is added into the gut compartments of Dual-organ plates and fluidically connected to the liver compartment

Results

Details are on PDF of poster.

Conclusion

The gut-liver MPS recapitulates the physiological conditions of oral drug dosing in the human (Figure 3-5). Made up entirely of primary human cells, this model enables for more predictive ADME and bioavailability studies compared to standard in vitro models (Figure 7). This human relevant gut-liver model offers a vast improvement in the methods used to study the pharmacokinetics of prodrugs that undergo CES metabolism, such as temocapril (Figure 6).