A new experimental model to study human drug responses. (23rd September 2020)

• Record Type: Journal Article
• Authors: Noh, Kyung Hee; Kang, Hyun Mi; Oh, Soo Jin; Lee, Ji-Yoon; Kim, Dae Hun; Kim, Mijin; Chung, Kyung-Sook; Son, Mi-Young; Kim, Dae-Soo; Cho, Hyun-Soo; Lee, Junhee; Lee, Duck-Gyu; Lim, Jung Hwa; Jung, Cho-Rok
• Is Part Of: Biofabrication. Volume 12:Number 4(2020)
• Publication Date: 2020-09-23
• Subjects: pharmacokinetics -- pharmacodynamics -- cell culture device -- cell differentiation -- In vivo-mimicking system; Biomedical engineering -- Periodicals; Tissue engineering -- Periodicals; Biomedical materials -- Microstructure -- Periodicals; Bioengineering -- Periodicals; 610.28
• DOI: 10.1088/1758-5090/abb652
• Languages: English
• ISSNs: 1758-5082

Abstract

Abstract: Accurate prediction of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics is critical for drug development. Oral drugs are particularly difficult because they are absorbed by the intestine and metabolized in the liver before systemic metabolism in vivo ; this is called the first-pass effect and is a critical factor for predicting oral bioavailability (BA). Here, we fabricated a new networking and circulating cell culture system (NCCS), mimicking the circulatory system and interaction of organs for studying the pharmacokinetic and pharmacodynamics of oral drugs in vitro . NCCS consisted of a micro-pump for circulating fluids, two types of multi-insert culture dishes for culturing different cell types, and an orbital shaker for mixing; flow rate and shaking-speed were controlled by weight-sensors and drivers. A first-pass effect test was performed using functionally differentiated HepaRG and Caco-2 cell lines, using a new modified spheroid forming unit (SFU) protocol. To verify the similarity of PK (first-pass effect) data of NCCS with the data from the human body, 15 reference drugs were chosen and their associated data were obtained by liquid chromatography-mass spectrometry analysis. NCCS generated absorption and metabolism data showed >70% similarity to human data respectively. NCCS can also be used to demonstrate species differences. Animal models are the primary basis for drug discovery, development, and testing. However, the weak correlation between humans and animals, particularly regarding absorption and metabolism, is a substantial limitation for the use of animal models. Here we compare human and mouse acetaminophen (APAP) metabolism using NCCS, and its application can be extended to assess cellular responses, such as efficacy and toxicity, simultaneously.