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

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.

[1]  William McLamb,et al.  Multi-Organ toxicity demonstration in a functional human in vitro system composed of four organs , 2016, Scientific Reports.

[2]  Jiajie Yu,et al.  In vitro 3D human small intestinal villous model for drug permeability determination. , 2012, Biotechnology and bioengineering.

[3]  W. Schoonen,et al.  Cytochrome P450 enzyme levels in HepG2 cells and cryopreserved primary human hepatocytes and their induction in HepG2 cells. , 2007, Toxicology in vitro : an international journal published in association with BIBRA.

[4]  Mandy B. Esch,et al.  Microfabricated mammalian organ systems and their integration into models of whole animals and humans. , 2013, Lab on a chip.

[5]  Frank Stahl,et al.  Comparison of primary human hepatocytes and hepatoma cell line Hepg2 with regard to their biotransformation properties. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[6]  Jiajie Yu,et al.  Microscale 3-D hydrogel scaffold for biomimetic gastrointestinal (GI) tract model. , 2011, Lab on a chip.

[7]  Aaron Sin,et al.  Development of a Microscale Cell Culture Analog To Probe Naphthalene Toxicity , 2008, Biotechnology progress.

[8]  D. Ingber,et al.  A human breathing lung‐on‐a‐chip , 2010, Annals of the American Thoracic Society.

[9]  Nam-Trung Nguyen,et al.  Microfluidic gut-on-a-chip with three-dimensional villi structure , 2017, Biomedical microdevices.

[10]  S. Alqahtani,et al.  Experimental models for predicting drug absorption and metabolism , 2013, Expert opinion on drug metabolism & toxicology.

[11]  Dong-June Park,et al.  A microfluidic cell culture device (μFCCD) to culture epithelial cells with physiological and morphological properties that mimic those of the human intestine , 2015, Biomedical Microdevices.

[12]  D. Ingber,et al.  Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow. , 2012, Lab on a chip.

[13]  Mandy B. Esch,et al.  Body-on-a-chip simulation with gastrointestinal tract and liver tissues suggests that ingested nanoparticles have the potential to cause liver injury. , 2014, Lab on a chip.

[14]  Tatiana Kniazeva,et al.  Performance and scaling effects in a multilayer microfluidic extracorporeal lung oxygenation device. , 2012, Lab on a chip.

[15]  Jong Hwan Sung,et al.  Microfluidic Gut-liver chip for reproducing the first pass metabolism , 2017, Biomedical Microdevices.

[16]  Majid Ebrahimi Warkiani,et al.  Flow-induced stress on adherent cells in microfluidic devices. , 2015, Lab on a chip.

[17]  W. R. Stahl,et al.  Organ Weights in Primates and Other Mammals , 1965, Science.

[18]  Lucas H. Hofmeister,et al.  Scaling and systems biology for integrating multiple organs-on-a-chip. , 2013, Lab on a chip.

[19]  Christopher Moraes,et al.  On being the right size: scaling effects in designing a human-on-a-chip. , 2013, Integrative biology : quantitative biosciences from nano to macro.

[20]  Michael Gertz,et al.  Prediction of Human Intestinal First-Pass Metabolism of 25 CYP3A Substrates from In Vitro Clearance and Permeability Data , 2010, Drug Metabolism and Disposition.

[21]  J. Mclaughlin,et al.  The gut‐skin axis in health and disease: A paradigm with therapeutic implications , 2016, BioEssays : news and reviews in molecular, cellular and developmental biology.

[22]  Jong Hwan Sung,et al.  A microfluidic device for a pharmacokinetic-pharmacodynamic (PK-PD) model on a chip. , 2010, Lab on a chip.

[23]  Michael L Shuler,et al.  Multi-cellular 3D human primary liver cell culture elevates metabolic activity under fluidic flow. , 2015, Lab on a chip.

[24]  Arti Ahluwalia,et al.  Allometric Scaling and Cell Ratios in Multi-Organ in vitro Models of Human Metabolism , 2014, Front. Bioeng. Biotechnol..

[25]  Sang-Hoon Lee,et al.  Spheroid-based three-dimensional liver-on-a-chip to investigate hepatocyte-hepatic stellate cell interactions and flow effects. , 2013, Lab on a chip.

[26]  L M Sweeney,et al.  A cell culture analogue of rodent physiology: Application to naphthalene toxicology. , 1995, Toxicology in vitro : an international journal published in association with BIBRA.

[27]  G. O'dwyer.  Agenda for change. , 2005, Nursing standard (Royal College of Nursing (Great Britain) : 1987).

[28]  F. Sonntag,et al.  A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents. , 2015, Lab on a chip.

[29]  Kristina Luthman,et al.  Caco-2 monolayers in experimental and theoretical predictions of drug transport1PII of original article: S0169-409X(96)00415-2. The article was originally published in Advanced Drug Delivery Reviews 22 (1996) 67–84.1 , 2001 .