Renal Toxicity Screening in Early-Stage Drug Discovery

Contact: Audrey Hu Whatsapp/hp: 0086 13880143964 Email: audrey.hu@wecistanche.com

Masanori

HIZUE Pfizer R&D Japan

Keywords: kidney

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The kidney is exposed to significant drug concentrations via systemic exposure because of high renal blood flow and a high rate of compound clearance. Drug-induced nephrotoxicity is increasingly recognized as a potential issue hampering clinical drug development. The failure of in vitro screening methods to identify nephrotoxic compounds can be attributed to many factors. The major one is the lack of valid in vitro models that fully recapitulate kidney phenotype.

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The development of in vitro models to successfully predict drug-induced kidney toxicity requires a solid understanding of the specific cellular targets, mode o action of nephrotoxic ants, and setting of reliable biomarkers of nephrotoxicity. The proximal tubule is of particular interest due to its active clearance, reabsorption, and intracellular concentration. Many drugs associated with kidney proximal tubule toxicity are hydrophilic, suggesting that active uptake via transporters drives the cell accumulation for such low permeable drugs.

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However, cells commonly used in vitro toxicity studies lack transporter expression, which can lead to false-negative results. In this presentation, our attempt for proximal tubule toxicity screening using transporter overexpression cell line Will be introduced and discussed. In addition, we will give an overview of recent approaches for the development of novel in vitro screening models which could be utilized to create a more physiologically relevant platform with the potential to improve the prediction value for proximal tubule toxicity screening.

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