3D gut-liver chip with a PK model for prediction of first-pass metabolism

Abstract

Accurate prediction of first-pass metabolism is essential for improving the time and cost efficiency of drug development process. Here, we have developed a microfluidic gut-liver co-culture chip that aims to reproduce the first-pass metabolism of oral drugs. This chip consists of two separate layers for gut (Caco-2) and liver (HepG2) cell lines, where cells can be co-cultured in both 2D and 3D forms. Both cell lines were maintained well in the chip, verified by confocal microscopy and measurement of hepatic enzyme activity. We investigated the PK profile of paracetamol in the chip, and corresponding PK model was constructed, which was used to predict PK profiles for different chip design parameters. Simulation results implied that a larger absorption surface area and a higher metabolic capacity are required to reproduce the in vivo PK profile of paracetamol more accurately. Our study suggests the possibility of reproducing the human PK profile on a chip, contributing to accurate prediction of pharmacological effect of drugs.

Gut–liver on a chip toward an in vitro model of hepatic steatosis

“…The gut cells can be cultured inside the chip in either 2D or 3D configurations (termed villi scaffold; Shim et al, ). The liver cells can be cultured either as a 2D monolayer, or as 3D spheroids (D. W. Lee, Ha, et al, ). In this study, HepG2 liver cells were cultured as 2D monolayer, and Caco‐2 gut cells were cultured as 2D monolayer or on the 3D villi scaffold.…”

“…The schematic diagram and pictures of the gut–liver chip is shown in Figure . The basic design of the chip was based on our previous studies (Choe et al, ; D. W. Lee, Ha, et al, ). Two separate flows are introduced to the top and bottom channels, representing the food ingestion and the blood flow, respectively.…”

“…The schematic diagram and pictures of the gut-liver chip is shown in Figure 2. The basic design of the chip was based on our previous studies (Choe et al, 2017;D. W. Lee, Ha, et al, 2017).…”

“…Another major advantage of an organ‐on‐a‐chip system is that it is capable of realizing the interaction between different organs (Sung et al, ; Sung, Kam, & Shuler, ). In particular, interactions between the gut and the liver have been the focus of intense research (Chen et al, ; Choe, Ha, Choi, Choi, & Sung, ; D. W. Lee, Ha, Choi, & Sung, ). For example, Leclerc et al, developed a microfluidic gut–liver chip to study the first‐pass metabolism of drugs (Bricks et al, ; Prot et al, ).…”

“…In particular, interactions between the gut and the liver have been the focus of intense research (Chen et al, 2017;Choe, Ha, Choi, Choi, & Sung, 2017;D. W. Lee, Ha, Choi, & Sung, 2017).…”