Microphysiological systems in absorption, distribution, metabolism, and elimination sciences

Abstract

The use of microphysiological systems (MPS) to support Adsorption, Distribution, Metabolism, and Elimination (ADME) sciences has grown substantially in the last decade in part driven by regulatory demands to move away from traditional animal-based safety assessment studies and industry desires to develop methodologies to efficiently screen and characterize drugs in the development pipeline. The past decade of MPS development has yielded great user-driven technological advances with the collective fine-tuning of cell culture techniques, fluid delivery systems, materials engineering, and performance enhancing modifications.The rapid advances in MPS technology have now made it feasible to evaluate critical ADME parameters within a stand-alone organ system or through interconnected organ systems. This review surveys current MPS developed for liver, kidney, and intestinal systems as stand-alone or interconnected organ systems, and evaluates each system for specific performance criteria recommended by regulatory authorities and MPS leaders that would render each system suitable for evaluating drug ADME. While some systems are more suitable for ADME type research than others, not all system designs were intended to meet the recently published desired performance criteria and are reported as a summary of initial proof-of-concept studies. Liver-Intestinal chip Caco-2/ 383-1132  cm 2 No data CYP3A-triazolam No data Gut-liver chip Caco-2/HepaRG fluorescein Morphology: F-actin Apigeninsulfation and glucuronide conjugates No data Liver-gut MPS

Clinical and Molecular Perspectives on Inflammation‐Mediated Regulation of Drug Metabolism and Transport

“…IL‐6‐mediated downregulation of CYP3A4 in a long‐term culture of micropatterned hepatocytes was reproducible within 5 different hepatocyte donors indicating a robust response of this hepatocyte culture format during long‐term studies 27 . In addition to novel long‐term primary human hepatocyte models, such as micropatterned hepatocytes and 3D hepatocytes, 27,36,99,100 more advanced hepatic models containing non‐parenchymal hepatic cells, such as Kupffer and endothelial cells, in static hepatic organoids, co‐cultures, or in microphysiological systems are potentially more physiological relevant models 36,99,101 . Findings derived from novel cell models may improve translation of DMET modulation by inflammation.…”

New and Emerging Research on Solute Carrier and ATP Binding Cassette Transporters in Drug Discovery and Development: Outlook From the International Transporter Consortium

“…Compared with traditional 2D cell models, these novel 3D cell systems, with varying levels of complexity, can better recapitulate morphological, microenvironmental, and functional features of human tissues, and therefore have demonstrated great promise as next generation in vitro tools to investigate physiology and disease mechanisms, drug disposition, toxicity, and response. 92,93 To date, a variety of 3D cell models and MPS, as stand-alone or interconnected organ systems, have been developed to represent major human ADME-related organs, such as the liver, gut, kidneys, and BBB. Their key features, limitations, and potential applications in drug discovery and development have been extensively reviewed.…”

“…The rapid advances in cell biology, tissue engineering, and microfabrication technologies have enabled the development of state‐of‐the‐art 3D cell culture models, such as spheroids, organoids, scaffolds, and microphysiological system (MPS; also known as organs‐on‐chips). Compared with traditional 2D cell models, these novel 3D cell systems, with varying levels of complexity, can better recapitulate morphological, microenvironmental, and functional features of human tissues, and therefore have demonstrated great promise as next generation in vitro tools to investigate physiology and disease mechanisms, drug disposition, toxicity, and response 92,93 . To date, a variety of 3D cell models and MPS, as stand‐alone or interconnected organ systems, have been developed to represent major human ADME‐related organs, such as the liver, gut, kidneys, and BBB.…”

Microphysiological Drug-Testing Platform for Identifying Responses to Prodrug Treatment in Primary Leukemia

“…By recapitulating complex physiological functions and tissue-tissue interactions of the human body in vitro, MPSs constitute more representative preclinical models of ADME for pharmacology and toxicology studies. MPSs offer the potential of improving disease modeling and conducting personalized-medicine studies in vitro, as they help to avoid issues related to interspecies differences resulting from the use of animal models 20,21,[28][29][30] . In particular, liver-on-chip MPSs, which mimic the physiological structure and function of liver, have been demonstrated to be more predictive models for pharmacology and toxicity studies in comparison to their 2D, well-based counterparts [30][31][32] .…”

“…By recapitulating complex physiological functions and tissue-tissue interactions of the human body in vitro, MPSs constitute more representative preclinical models of ADME for pharmacology and toxicology studies. MPSs offer the potential of improving disease modeling and conducting personalized-medicine studies in vitro, in particular, as they help to avoid issues related to interspecies differences resulting from the use of animal models 20,21,[28][29][30] . For instance, a multiorgan MPS was developed to recapitulate the metabolism of tolcapone, a drug used to treat Parkinson's disease.…”