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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-016-1918-1) contains supplementary material, which is available to authorized users.

Effects of the kinase inhibitor sorafenib on heart, muscle, liver and plasma metabolism in vivo using non‐targeted metabolomics analysis

“…Since sorafenib causes cardiotoxicity necessitating drug discontinuation in some patients (Schmidinger et al, ; Hall et al, ; Escalante et al, ), as well as liver toxicity associated with mitochondrial dysfunction in rodents (Zhang et al, ), we applied a non‐targeted metabolomics analysis using GC/MS to both the heart and liver after 2 weeks of treatment that induced cardiac toxicity (Figure ). We assayed skeletal muscle (quadriceps femoris) and plasma collected in parallel to identify if myocardium and striated muscle metabolism are affected similarly and if any of these observed alterations could be monitored by any biomarkers in the plasma.…”

“…Recent studies of 31 small‐molecule KIs approved for use in humans as of November 2016 found that sorafenib was one of three KIs that were hepatotoxic at concentrations equal to the C max and indicated that mitochondrial toxicity was likely contributing to the liver toxicity (Zhang et al, ). Treating animals with sorafenib decreases body weight, an effect also reported in humans, suggesting that sorafenib treatment may lead to fundamental alterations in metabolism (Duran et al, ; Kuczynski et al, ).…”

Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

“…However, as far as TKI are concerned, very few data support the role of RM rather than the parent drug in TKI‐induced hepatotoxicity; these cases are discussed in this section. However, reporting the current state of knowledge of the entire spectrum of toxicity mechanisms at a cellular level is beyond the scope of this review …”

Drug rechallenge following drug‐induced liver injury

“…Specific features identify drugs associated with high rates of DILI and positive rechallenge: daily dose exceeding 50 mg, predominant hepatic metabolism, hepatocellular injury, and evidence of immunoallergic injury or mitochondrial impairment in vitro . Hepatotoxicity is evident in most drugs with preclinical testing exhibiting: reactive metabolites, marked metabolism‐dependent cytochrome p‐450 inhibition (with >5‐fold change in IC 50 ), covalent protein binding (≥200 pmol eq/mg protein), reactive oxygen species, glutathione adduct formation, lipophilicity (logP≥3), BSEP inhibition, cellular ATP depletion, mitochondrial toxicity, or cytotoxicity .…”