Advances in organ-on-chip for drug transporter study: Key insights and hurdles

Membrane transporters play a central role in the absorption, distribution, metabolism, and elimination of drugs. Beyond drug handling, these transporters regulate the transport of endogenous metabolites, contributing to physiological homeostasis. Their activity is regulated not only by intrinsic cellular mechanisms but also by signals from distant organs. Understanding these processes is crucial for accurately predicting both local and systemic pharmacokinetics, as transporter function influences drug concentrations and effects at target tissues and throughout the organism. However, most current in vitro models do not recapitulate interorgan interactions or the dynamic regulation of transporter function. Microphysiological systems, particularly organ-on-chip, offer a promising approach to studying transporter biology in a more integrated and physiologically relevant context. This review provides an overview of the development and application of organ-on-chip technologies to investigate drug transporters and their regulation. Although significant technical progress has been made, these systems often remain focused on engineering or industrial goals, with limited impact on fundamental biological questions. Moreover, the high degree of customization and widespread use of homemade organ-on-chip models, with diverse materials, geometries, and cell sources, have created substantial barriers to reproducibility and cross-laboratory comparison. We here assess the current state of the field and identify gaps in modeling transporter regulation and interorgan communication. We also explore the potential of organ-on-chip to advance our understanding of systemic pharmacology. This review aims to reposition organ-on-chip platforms not only as technological demonstrators but also as experimental systems capable of generating new biological insights into transporter function and organ crosstalk. SIGNIFICANCE STATEMENT: Membrane transporters are central regulators of drug disposition and systemic homeostasis, yet their interorgan regulation remains poorly captured by conventional models. This review highlights how organ-on-chip technologies can bridge this gap, enabling mechanistic investigation of transporter function and advancing predictive, human-relevant pharmacology.