Drug Metab Dispos. 2025 Dec;53(12):100188. doi: 10.1016/j.dmd.2025.100188. Epub 2025 Oct 22.
ABSTRACT
The drug discovery and development process faces significant challenges, including high attrition rates and substantial financial investment, in part due to the limitations of traditional 2-dimensional (2D) cell culture systems and animal models to predict human drug metabolism, efficacy, and toxicity. This review highlights the emergence of novel in vitro human cell culture and organoid systems, such as 3-dimensional (3D) cultures, self-assembling organoids, induced pluripotent stem cell-derived models, and microphysiological system or organ-on-a-chip systems, as transformative solutions to the issues raised when extrapolating from 2D cell culture. These advanced platforms offer enhanced physiological relevance by better recapitulating complex in vivo microenvironments, thus improving the predictability and accuracy of preclinical drug assessment. In this study, we systematically cover the utility of these advanced systems in studying drug metabolism and toxicology across key organs like the liver, intestine, and kidney, emphasizing their advantages over conventional models in terms of cellular diversity, architectural complexity, and long-term functional maintenance. We also discuss the potential of integrating these novel systems into the drug development pipeline, particularly their compatibility with high-throughput screening and their alignment with the 3Rs principle (replacement, reduction, and refinement) for ethical research. Despite their immense promise, challenges remain; including the lack of standardized protocols, the complexity of data analysis, and the need for further advancements in vascularization, innervation, and immune component integration. We conclude by exploring future directions, including the crucial role of artificial intelligence and machine learning in analyzing complex datasets and the potential for personalized medicine through patient-derived organoids. Overcoming these challenges will be vital for these innovative platforms to revolutionize pharmaceutical development, leading to safer, more effective, and more efficiently produced pharmaceuticals. SIGNIFICANCE STATEMENT: This article reviews the design, construction, and implementation of novel in vitro cell culture and organoid systems for preclinical drug metabolism and pharmacokinetics and toxicology studies. As such, it serves as a resource for interested parties who would like to learn about, and implement, these cutting-edge technologies into their drug discovery and development workflow.
PMID:41252796 | DOI:10.1016/j.dmd.2025.100188