Zhang, Jun published the artcileCytotoxicity of 34 FDA approved small-molecule kinase inhibitors in primary rat and human hepatocytes, Safety of N-(2-Chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide hydrate, the publication is Toxicology Letters (2018), 138-148, database is CAplus and MEDLINE.
Of the 34 FDA approved oral small-mol. kinase inhibitors (KI), 23 (68%) have warnings for hepatotoxicity in product labeling. To better understand the mechanisms of KI hepatotoxicity and whether such effects can be predicted, the authors examined 34 KIs for cytotoxicity in primary rat and human hepatocytes. The hepatocytes were treated with KIs at ten concentrations normalized to maximal therapeutic blood levels (Cmax). At 5 and 24 h post treatment, lactate dehydrogenase or alanine amtransferase leakage, caspase 3/7 activities and cellular ATP levels were measured. At 1 to 100-fold Cmax, while 5 KIs were neither toxic to human nor rat hepatocytes, 3 KIs showed similar cytotoxicity in both species and 26 KIs showed species-biased cytotoxicity, with 16 KIs being more toxic to human hepatocytes and 10 KIs being more toxic to rat hepatocytes. At concentrations of 1-, 2.5-, 5-, 10-, 100-fold Cmax, the number of cytotoxic KIs in human hepatocytes was 4, 8, 11, 14 and 27, resp., and the corresponding number in rat hepatocytes was 1, 4, 9, 12 and 27, resp. When hepatocyte cytotoxicity at 100-fold Cmax was used to predict KI clin. hepatotoxicity reflected in product labeling, the accuracy was 0.65 with human hepatocytes and 0.59 with rat cells. When the criterion of daily dose ≥100 mg or Cmax ≥1.1 μM was used to predict KI hepatotoxicity, the accuracy was 0.56 or 0.47, resp. These results suggest both indirect and direct drug-induced hepatocyte toxicity may contribute to the mechanisms of KI-induced hepatotoxicity seen clin. and use of primary hepatocytes is a useful in vitro model to help predict such toxicity.
Toxicology Letters published new progress about 863127-77-9. 863127-77-9 belongs to piperazines, auxiliary class TGF-beta/Smad,Bcr-Abl,Natural product, name is N-(2-Chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide hydrate, and the molecular formula is C7H5BClNO2, Safety of N-(2-Chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide hydrate.
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https://en.wikipedia.org/wiki/Piperazine,
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