Metodo alternativo per il rilevamento dell’epatotossicità

[Salman R. Khetani, Chitra Kanchagar, Okechukwu Ukairo, Stacy Krzyzewski, Amanda Moore, Julianne Shi, Simon Aoyama, Michael Aleo and Yvonne Will. The Use of Micropatterned Co-cultures to Detect Compounds that Cause Drug induced Liver Injury in Humans. Toxicol. Sci. (2013) 132 (1): 107-117.]

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Since drug induced liver injury (DILI) remains a major reason for late stage drug attrition, predictive assays are needed that can be deployed throughout the drug discovery process Clinical DILI can be predicted with a sensitivity of ~50% and a false positive rate of ~5% using 24 hour cultures of primary sandwich cultured human hepatocytes and imaging of four cell injury endpoints (Xu et al., 2008). We hypothesized that long-term drug dosing in a stable model of primary hepatocytes (micropatterned co-cultures or MPCCs) could provide for increased predictivity over short-term dosing paradigms. We used MPCCs with either primary human or rat hepatocytes to understand possible species differences along with standard end-points (glutathione levels, ATP levels, albumin and urea secretion) to test 45 drugs either known or not known to cause clinical DILI. Human MPCCs correctly detected 23 of 35 compounds known to cause DILI (65.7% sensitivity) with a false positive rate of 10% for the 10 negative compounds tested. Rat MPCCs correctly detected 17 of 35 DILI compounds (48.6% sensitivity) and had a higher false positive rate than human MPCCs (20% versus 10%). For drugs with the most DILI concern, human MPCCs displayed a sensitivity of 100%. Furthermore, MPCCs were able to detect relative clinical toxicities of structural drug analogs. In conclusion, MPCCs showed superiority over conventional short-term cultures for predictions of clinical DILI and human MPCCs were more predictive for human liabilities than their rat counterparts.


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