期刊
TOXICOLOGY IN VITRO
卷 63, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tiv.2019.104752
关键词
Microphysiological systems; Tissue-on-a-chip; Kidney; Pharmacokinetics; Renal clearance; Tubular reabsorption
类别
资金
- U.S. National Center for Advancing Translational Sciences [U24 TR001950, UH3 TR000504, 5UH3 TR000504, UG3 TR002158]
- U.S. National Institute of Environmental Health Sciences [T32 ES026568]
Kidney is a major route of xenobiotic excretion, but the accuracy of preclinical data for predicting in vivo clearance is limited by species differences and non-physiologic 2D culture conditions. Microphysiological systems can potentially increase predictive accuracy due to their more realistic 3D environment and incorporation of dynamic flow. We used a renal proximal tubule microphysiological device to predict renal reabsorption of five compounds: creatinine (negative control), perfluorooctanoic acid (positive control), cisplatin, gentamicin, and cadmium. We perfused compound-containing media to determine renal uptake/reabsorption, adjusted for nonspecific binding. A physiologically-based parallel tube model was used to model reabsorption kinetics and make predictions of overall in vivo renal clearance. For all compounds tested, the kidney tubule chip combined with physiologically-based modeling reproduces qualitatively and quantitatively in vivo tubular reabsorption and clearance. However, because the in vitro device lacks filtration and tubular secretion components, additional information on protein binding and the importance of secretory transport is needed in order to make accurate predictions. These and other limitations, such as the presence of non-physiological compounds such as antibiotics and bovine serum albumin in media and the need to better characterize degree of expression of important transporters, highlight some of the challenges with using microphysiological devices to predict in vivo pharmacokinetics.
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