A novel multi-parametric high content screening assay in ciPTEC-OAT1 to predict drug-induced nephrotoxicity during drug discovery

Sjögren, Anna-Karin; Breitholtz, Katarina; Ahlberg, Ernst; Milton, Lucas; Forsgard, Malin; Persson, Mikael; Stahl, Simone H.; Wilmer, Martijn J.; Hornberg, Jorrit J.

doi:10.1007/s00204-018-2284-y

Organ Toxicity and Mechanisms
Published: 24 August 2018

A novel multi-parametric high content screening assay in ciPTEC-OAT1 to predict drug-induced nephrotoxicity during drug discovery

Anna-Karin Sjögren¹,
Katarina Breitholtz³,
Ernst Ahlberg⁵,
Lucas Milton⁶,
Malin Forsgard¹,
Mikael Persson¹,
Simone H. Stahl⁴,
Martijn J. Wilmer⁷ &
Jorrit J. Hornberg²

Archives of Toxicology volume 92, pages 3175–3190 (2018)Cite this article

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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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Acknowledgements

We kindly thank Johanna Sagemark for performing the clustering analysis and Magnus Söderberg for scientific discussions.

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Authors and Affiliations

CVRM Safety, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca R&D, Gothenburg, Sweden
Anna-Karin Sjögren, Malin Forsgard & Mikael Persson
RIA Safety, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca R&D, Gothenburg, Sweden
Jorrit J. Hornberg
Mechanistic Safety and ADME Sciences, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca R&D, Gothenburg, Sweden
Katarina Breitholtz
Mechanistic Safety and ADME Sciences, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca R&D, Cambridge, UK
Simone H. Stahl
Data Science and AI, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca R&D, Gothenburg, Sweden
Ernst Ahlberg
DMD, CVRM, IMED Biotech Unit, AstraZeneca R&D, Gothenburg, Sweden
Lucas Milton
Department of Pharmacology and Toxicology, Radboud Institute of Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands
Martijn J. Wilmer

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Anna-Karin Sjögren
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Katarina Breitholtz
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Ernst Ahlberg
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Lucas Milton
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Malin Forsgard
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Mikael Persson
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Simone H. Stahl
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Martijn J. Wilmer
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Jorrit J. Hornberg
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Correspondence to Anna-Karin Sjögren.

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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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Received: 09 July 2018
Accepted: 06 August 2018
Published: 24 August 2018
Issue Date: October 2018
DOI: https://doi.org/10.1007/s00204-018-2284-y

Keywords

Nephrotoxicity
Drug safety
Kidney
ciPTEC
High content imaging