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NCTR Research Highlights

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Current Highlight from January 6, 2017

Effects of Small-Molecule Kinase Inhibitors on Isolated Rat Liver Mitochondria      

Scientists from NCTR and CDER utilized isolated rat liver mitochondria to test 31 FDA-approved small-molecule kinase inhibitors (KIs) for mitochondrial toxicity in vitro and showed that only three (all of which are hepatotoxic in humans) caused mitochondrial toxicity at concentrations equivalent to the therapeutic maximal blood concentrations (Cmax). At this concentration, mitochondrial toxicity showed a 100% positive predictive value (PPV) and a negative predictive value (NPV) of 32%.  Conversely, at 100-fold Cmax, mitochondrial toxicity had a PPV of 72% and a NPV of 33%.  Although in vitro mitochondrial toxicity assessments have been proposed as a useful tool to predict the hepatotoxicity of chemicals, these findings suggest that its predictive power for KI-induced hepatotoxicity in humans is limited to positive predictions at Cmax concentrations.  A manuscript reporting the results of this study is available online at Archives of Toxicologydisclaimer icon. 

For more information, please contact Qiang Shi Ph.D., Innovative Safety and Technologies Branch, Division of Systems Biology, FDA/NCTR or William Mattes Ph.D., DABT, Division Director, Division of Systems Biology, FDA/NCTR.    

Contact FDA

National Center for Toxicological Research

Food and Drug Administration

3900 NCTR Road

Jefferson, AR 72079

Page Last Updated: 01/19/2017
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