Abstract
Drug-induced nephrotoxicity is a major concern in the clinic and hampers the use of available treatments as well as the development of innovative medicines. It is typically discovered late during drug development, which reflects a lack of in vitro nephrotoxicity assays available that can be employed readily in early drug discovery, to identify and hence steer away from the risk. Here, we report the development of a high content screening assay in ciPTEC-OAT1, a proximal tubular cell line that expresses several relevant renal transporters, using five fluorescent dyes to quantify cell health parameters. We used a validation set of 62 drugs, tested across a relevant concentration range compared to their exposure in humans, to develop a model that integrates multi-parametric data and drug exposure information, which identified most proximal tubular toxic drugs tested (sensitivity 75%) without any false positives (specificity 100%). Due to the relatively high throughput (straight-forward assay protocol, 96-well format, cost-effective) the assay is compatible with the needs in the early drug discovery setting to enable identification, quantification and subsequent mitigation of the risk for nephrotoxicity.
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We kindly thank Johanna Sagemark for performing the clustering analysis and Magnus Söderberg for scientific discussions.
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MJ Wilmer is an employee of Radboud University who holds a patent on ciPTEC. All other authors declare that they have no conflict of interest.
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Sjögren, AK., Breitholtz, K., Ahlberg, E. et al. A novel multi-parametric high content screening assay in ciPTEC-OAT1 to predict drug-induced nephrotoxicity during drug discovery. Arch Toxicol 92, 3175–3190 (2018). https://doi.org/10.1007/s00204-018-2284-y
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DOI: https://doi.org/10.1007/s00204-018-2284-y