Abstract

The liver is the primary organ responsible for the detoxification and metabolism of drugs. To date, a lack of preclinical models that accurately emulate drug metabolism by the human liver presents a significant challenge in the drug development pipeline, particularly for predicting drug efficacy and toxicity. In recent years, emerging microfluidic-based organ-on-a-chip (OoC) technologies, combined with human induced pluripotent stem cell (hiPSC) technology, present a promising avenue for the complete recapitulation of human organ biology in a patient-specific manner. However, hiPSC-derived organoids and liver-on-a-chip models have so far failed to sufficiently express cytochrome P450 monooxygenase (CYP450) enzymes, the key enzymes involved in first-pass metabolism, which limits the effectiveness and translatability of these models in drug metabolism studies. This review explores the potential of innovative organoid and OoC technologies for studying drug metabolism and discusses their existing drawbacks, such as low expression of CYP450 genes. Finally, we postulate potential approaches for enhancing CYP450 expression in the hope of paving the way toward developing novel, fully representative liver drug-metabolism models.

MeSH

Enzymes, Pharmaceutical Preparations, Microscopy, Electron, Scanning Transmission, Liver, Induced Pluripotent Stem Cells, Cytochrome P-450 Enzyme System, Cytochromes, Organoids

Cited by

• Developments and Applications of Liver-on-a-Chip Technology-Current Status and Future Prospects. Biomedicines, 2025
• Current hPSC-derived liver organoids for toxicity testing: Cytochrome P450 enzymes and drug metabolism. Toxicol Res, 2025