title: Effects of 31 FDA approved small-molecule kinase inhibitors on isolated rat liver mitochondria.
abstract: The FDA has approved 31 small-molecule kinase inhibitors (KIs) for human use as of November 2016, with six having black box warnings for hepatotoxicity (BBW-H) in product labeling. The precise mechanisms and risk factors for KI-induced hepatotoxicity are poorly understood. Here, the 31 KIs were tested in isolated rat liver mitochondria, an in vitro system recently proposed to be a useful tool to predict drug-induced hepatotoxicity in humans. The KIs were incubated with mitochondria or submitochondrial particles at concentrations ranging from therapeutic maximal blood concentrations (Cmax) levels to 100-fold Cmax levels. Ten endpoints were measured, including oxygen consumption rate, inner membrane potential, cytochrome c release, swelling, reactive oxygen species, and individual respiratory chain complex (I-V) activities. Of the 31 KIs examined only three including sorafenib, regorafenib and pazopanib, all of which are hepatotoxic, caused significant mitochondrial toxicity at concentrations equal to the Cmax, indicating that mitochondrial toxicity likely contributes to the pathogenesis of hepatotoxicity associated with these KIs. At concentrations equal to 100-fold Cmax, 18 KIs were found to be toxic to mitochondria, and among six KIs with BBW-H, mitochondrial injury was induced by regorafenib, lapatinib, idelalisib, and pazopanib, but not ponatinib, or sunitinib. Mitochondrial liability at 100-fold Cmax had a positive predictive power (PPV) of 72% and negative predictive power (NPV) of 33% in predicting human KI hepatotoxicity as defined by product labeling, with the sensitivity and specificity being 62% and 44%, respectively. Similar predictive power was obtained using the criterion of Cmax ≥1.1 µM or daily dose ≥100 mg. Mitochondrial liability at 1-2.5-fold Cmax showed a 100% PPV and specificity, though the NPV and sensitivity were 32% and 14%, respectively. These data provide novel mechanistic insights into KI hepatotoxicity and indicate that mitochondrial toxicity at therapeutic levels can help identify hepatotoxic KIs.
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.|Biomedical Engineering 2016, University of Arkansas, Fayetteville, AR, 72701, USA.
authors.forename: Alec
authors.initials: A
authors.lastname: Salminen
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Qiangen
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: White
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: James
authors.initials: J
authors.lastname: Greenhaw
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Ren
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bryant
authors.affiliation: ProNatural Brands LLC, 1174 Southwest 5th Avenue, Boca Raton, FL, 33432, USA.
authors.forename: William
authors.initials: W
authors.lastname: Salminen
authors.affiliation: Division of Cardiovascular and Renal Products, Office of New Drugs I, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Papoian
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: William
authors.initials: W
authors.lastname: Mattes
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA. qiang.shi@fda.hhs.gov.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Shi
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004348:Drug Labeling; D005260:Female; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012307:Risk Factors; D012680:Sensitivity and Specificity; D013045:Species Specificity
chemical_list: D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D010100:Oxygen
keywords: Drug induced liver injury; Hepatotoxicity; Kinase inhibitor; Mitochondrion; Submitochondrial particles