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 Toxicology.
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.
NCTR Research Highlights Archives
2017-NCTR Research Highlights 2016-NCTR Research Highlights 2015-NCTR Research Highlights 2014-NCTR Research Highlights[ARCHIVED] 2013-NCTR Research Highlights[ARCHIVED] 2012-NCTR Research Highlights[ARCHIVED] 2011-NCTR Research Highlights[ARCHIVED] 2010-NCTR Research Highlights[ARCHIVED] 2009-NCTR Research Highlights[ARCHIVED] 2008-NCTR Research Highlights[ARCHIVED] 2007-NCTR Research Highlights[ARCHIVED] 2006-NCTR Research Highlights[ARCHIVED]