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In vitro models for accurate prediction of renal tubular xenobiotic transport in vivo

To date, the most representative model of the proximal tubule has been the primary culture of human PTC cells onto permeable filter supports.

These form monolayers with transepithelial epithelial electrical resistance (TEER) values around 100 U cm² and retain a high abundance of key transporters. Net flux of substrates
mediated by the polar distribution of key transporters, including PAH, creatinine, and urate, has been demonstrated. Importantly, the same model is highly predictive of nephrotoxicity against a test panel of compounds with well-defined in vivo renal outcomes. Primary PTC models of humans and dogs have proved valuable in identifying species differences in the handling of
substrates illustrating the importance of deriving similar in vitro models of PTC from key preclinical species as a tool to understand species differences in renal handling of drugs. With the widespread establishment of tissue banks to generate primary PTCs, the availability of fresh kidneys has improved dramatically. Inter-kidney variation is remarkably small. Variability was recently
published for six endpoints of toxicity, over 23 kidneys.

Freshly isolated proximal tubule cells arguably remain the gold standard of both transepithelial flux and nephrotoxicity prediction assays.

Published

16th April, 2021

Published by

Jelle Vriend, Keith R. Pye, Colin Brown
Current Opinion in Toxicology. 2021; 25: 15-22

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