Genome edited intestine liver on a chip system for integrated intestinal hepatic drug absorption and metabolism evaluation

Evaluation of the intestinal absorption and hepatic metabolism is crucial to the development of orally administered drugs. Previous evaluation systems have assessed intestinal epithelial cells and hepatocytes separately. To develop an experimental system that accounts for drug transfer from the intestine to the liver, we generated a genome-edited intestine-liver-on-a-chip system (genome-edited chip) by incorporating high drug metabolism capacity genome-edited Caco-2 cells in the top channel and CYPs-UGT1A1 KI-HepG2 cells in the bottom channel of a polydimethylsiloxane-based microfluidic device. We demonstrated that the genome-edited chip enables simultaneous evaluation of drug absorption and metabolism by allowing sample collection from both the top and bottom channels. We then confirmed the feasibility of the system in experiments showing that the concentrations of CYP3A4 metabolites decreased under the influence of itraconazole or bergamottin, known CYP3A4 inhibitors. These results validate the utility of the genome-edited chip as a convenient and cost-effective tool for drug absorption and metabolism experiments that takes into account the influence of both the small intestine and liver. This system represents a significant advancement in pharmacokinetic evaluation, offering a more integrated approach to understanding drug behavior in the body. By mimicking the sequential process of intestinal absorption followed by hepatic metabolism, the genome-edited chip provides a more physiologically relevant model compared to traditional single-cell type systems.