Development of Microphysiological Models for the Assessment of Xenobiotic and Endobiotic Absorption and Disposition

Abstract

Animal models and in vitro systems have long been relied upon to provide insights into the toxicology, pharmacodynamics and pharmacokinetics of investigational drug candidates before they are administered to human subjects. In this respect, these systems serve as crucial gatekeepers, protecting human subjects from some harmful prospective investigational drugs and also steering pharmaceutical researchers away from expending valuable time and resources on unpromising drug candidates. Despite the remarkable accomplishments in reducing both the drug attrition rates in clinical studies, existing preclinical models are far from refined systems. The growing recognition of crucial interspecies differences has prompted greater interest in human-derived in vitro preclinical models. However, cellular and subcellular systems, when separated from the crucial architecture of their native functional units (e.g. villi, acini, and nephrons), lose the capacity to execute physiological functions that are dependent on their in vivo microenvironment. To this end, we have pursued the development of in vitro microphysiological systems that are designed to better reflect the native environment of in vivo organ tissues. Herein are described specific efforts to develop microphysiological systems for the assessment of xenobiotic and endobiotic metabolism and disposition in the human small intestine and renal proximal tubule. The renal proximal tubule microphysiological system displayed numerous hallmark structural features and recapitulated of a many important physiological functions of the renal proximal tubule in vivo. Once validated, the kidney proximal tubule microphysiological system was used to characterize the megalin-mediated pathway through which vitamin D metabolites access their major site of bioactivation in humans, the proximal tubule epithelium. These findings are of broad importance given that the bioactive metabolite of vitamin D is a potent hormone with a demonstrated capacity to regulate the expression of xenobiotic-metabolizing enzymes and transporters.