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Abstract
The compound [3-(1H-benzimidazol-2-methylene)-5-(2-methylphenylaminosulfo)-2-indolone], known as Indo5, is a novel selective inhibitor of c-Met and Trks, and it is a promising anticancer candidate against hepatocellular carcinoma (HCC). Assessing the pharmacokinetic properties, tissue distribution, and toxicity of Indo5 is critical for its medicinal evaluation. A series of sensitive and specific liquid chromatography-tandem mass spectrometry methods were developed and validated to determine the concentration of Indo5 in rat plasma and tissue homogenates. These methods were then applied to investigate the pharmacokinetics and tissue distribution of Indo5 in rats. After intravenous injection of Indo5, the maximum concentration (Cmax) and the time at which Cmax was reached (Tmax) were 1,565.3 ± 286.2 ng/ml and 1 min, respectively. After oral administration, Cmax and Tmax were 54.7 ± 10.4 ng/ml and 2.0 ± 0.48 h, respectively. We calculated the absolute oral bioavailability of Indo5 in rats to be 1.59%. Following intravenous injection, the concentrations of Indo5 in various tissues showed the following order: liver > kidney ≈ heart > lung ≈ large intestine ≈ small intestine ≈ stomach > spleen > brain ≈ testes; hence, Indo5 distributed highest in the liver and could not cross the blood–brain or blood–testes barriers. Continuous injection of Indo5 for 21 days did not lead to liver injury, considering unchanged ALT and AST levels, normal histological architecture of the liver, and normal number and frequencies of immune cells in the liver, indicating a very low toxicity of Indo5 in vivo. Collectively, our findings provide a comprehensive understanding of the biological actions of Indo5 in vivo and further support its development as an antitumor treatment for HCC patients.
Highlights
Hepatocellular carcinoma (HCC) accounts for about 80–90% of primary liver cancers (Llovet et al, 2008; Pan et al, 2011; Stewart and Wild, 2014; Sia et al, 2017)
The first targeted, systemic therapy approved for the treatment of advanced HCC by the US Food and Drug Administration (FDA) in 2007 was based on the multityrosine kinase inhibitor sorafenib (Shen et al, 2013; Stotz et al, 2015)
Our method demonstrated high selectivity given that there was no interference in the analyte peaks with those obtained using standards or the internal standard (IS)
Summary
Hepatocellular carcinoma (HCC) accounts for about 80–90% of primary liver cancers (Llovet et al, 2008; Pan et al, 2011; Stewart and Wild, 2014; Sia et al, 2017). Molecular-targeted therapies have been used to treat various types of cancer, including liver cancer. This approach inhibits the growth of tumor cells by interfering with molecules involved in carcinogenesis; molecular-targeted therapy is more selective and specific than cytotoxic chemotherapy (Alqahtani et al, 2019). The first targeted, systemic therapy approved for the treatment of advanced HCC by the US Food and Drug Administration (FDA) in 2007 was based on the multityrosine kinase inhibitor sorafenib (Shen et al, 2013; Stotz et al, 2015). Development of novel molecular-targeted therapies for HCC with low toxicity or fewer adverse effects is urgently required
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