A novel multi-parametric high content screening assay in ciPTEC-OAT1 to predict drug-induced nephrotoxicity during drug discovery.
Arch Toxicol
; 92(10): 3175-3190, 2018 10.
Article
em En
| MEDLINE
| ID: mdl-30155723
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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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Testes de Toxicidade
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Ensaios de Triagem em Larga Escala
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Rim
Tipo de estudo:
Diagnostic_studies
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Guideline
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Prognostic_studies
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Risk_factors_studies
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Screening_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article