Health & Environmental Research Online (HERO)


Print Feedback Export to File
6320196 
Journal Article 
Predicting tubular reabsorption with a human kidney proximal tubule tissue-on-a-chip and physiologically-based modeling 
Sakolish, C; Chen, ZW; Dalaijamts, C; Mitra, K; Liu, YN; Fulton, T; Wade, TL; Kelly, EJ; Rusyn, I; Chiu, WHA 
2020 
Yes 
Toxicology In Vitro
ISSN: 0887-2333
EISSN: 1879-3177 
63 
104752 
English 
31857146 
WOS:000509613100029 
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 non-specific 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. 
Microphysiological systems; Tissue-on-a-chip; Kidney; Pharmacokinetics; Renal clearance; Tubular reabsorption