Application of human liver cell models in drug development and toxicity studies: The role of membrane transporters.

The critical involvement of hepatic transporters in both physiological and pathological processes, including metabolic diseases, drug metabolism, and toxicity, represents a key issue in pharmacology. The expression and localization of transporters involved in hepatic functions are especially important in new drug development and toxicology studies. Because of major species differences in transporter expression, localization, and substrate recognition, the value of animal experiments is limited in this regard, and human liver cell preparations are already available to allow relevant in vitro studies. Currently, the gold standard for in vitro studies is the primary human liver cell preparation. However, the interindividual heterogeneity, low reproducibility, and high price of such preparations are prohibiting their widespread use. Hepatocytes derived from liver tumors are widely used in toxicology studies, but each of these cell lines has specific advantages and shortcomings. Stem cell-based liver cell preparations, especially spheroids and organoids derived from human induced pluripotent stem cells, may serve as a new toolbox for studying a variety of membrane transporters and complex metabolic interactions in human hepatocytes. These advanced preparations, although currently somewhat premature, should provide an excellent basis for comprehensive in vitro functional assays. The present paper provides a comparative review of our current understanding of the pharmacological relevance of hepatic transporters, their interactions with the key players of general drug metabolism, their complex regulation, as well as the recent methodologies to apply human-relevant in vitro systems in drug development and toxicology studies. SIGNIFICANCE STATEMENT: This review addresses the critical need for advanced human liver models in drug development, moving away from animal testing and inadequate tumor-derived cells. By evaluating emerging stem cell-derived 2D and 3D cultures, it highlights the often-overlooked role of membrane transporters-crucial for understanding how drugs enter and exit cells. This work provides a roadmap for creating physiologically accurate models to better predict drug safety, efficacy, and toxicity in humans.