A Laminated Microfluidic Device for Comprehensive Preclinical Testing in the Drug ADME Process.

Fan An,Yang Liu,Weijie Zhao,Zhigang Gao,Ning Fang,Yong Luo,Yueyang Qu,Bingcheng Lin

doi:10.1038/srep25022

Abstract

New techniques are urgently needed to replace conventional long and costly pre-clinical testing in the new drug administration process. In this study, a laminated microfluidic device was fabricated to mimic the drug ADME response test in vivo. This proposed device was loaded and cultured with functional cells for drug response investigation and organ tissues that are involved in ADME testing. The drug was introduced from the top of the device and first absorbed by the Caco-2 cell layer, and then metabolized by the primary hepatocyte layer. It subsequently interacted with the MCF-7 cell layer, distributed in the lung, heart and fat tissues, and was finally eliminated through the dialysis membrane. Throughout this on-chip ADME process, the proposed device can be used as a reliable tool to simultaneously evaluate the drug anti-tumor activity, hepatotoxicity and pharmacokinetics. Furthermore, this device was proven to be able to reflect the hepatic metabolism of a drug, drug distribution in the target tissues, and the administration method of a drug. Furthermore, this microdevice is expected to reduce the number of drug candidates and accelerate the pre-clinical testing process subject to animal testing upon adaptation in new drug discovery.

Highlights

The traditional new drug discovery process is extremely costly, time-consuming and inefficient, and it has retarded fast advances in the drug industry and improvements in human health
Drug candidates that survive the preclinical testing may fail during the animal testing or clinical trial stage because the data obtained from in vitro drug screening platforms, such as a 96-well plate, cannot be extrapolated to the real body of animals or humans
A drug candidate experiences a complex in vivo ADME process

Summary

Introduction

The traditional new drug discovery process is extremely costly, time-consuming and inefficient, and it has retarded fast advances in the drug industry and improvements in human health. We attempted to recreate the ADME process in vitro and develop a platform for drug screening. To this end, we selected a microfluidic chip as the new ADME screening platform because it may allow the co-culture of multiple types of functional cells and a comprehensive analysis of cells, drug candidates and their metabolites. Cell chips have been intensively used for drug screening, either for toxicity[15], efficacy[16] or pharmacokinetics[12] They have even been transformed into “organ-on-a-chip17”, “body-on-a-chip11” and “human-on-a-chip18” devices that have demonstrated a strong potential to revolutionize drug discovery. We attempted to develop a new type of cell co-culture chip for preclinical testing featuring an artificial ADME process

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Conclusion