Ketoconazole-induced hepatic phospholipidosis in the mouse and its association with de-N-acetyl ketoconazole
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Does the circulating ketoconazole metabolite N-deacetyl ketoconazole contribute to the drug-drug interaction potential of the parent compound?
2022, European Journal of Pharmaceutical SciencesCitation Excerpt :According to very early publications on ketoconazole, its main metabolism in humans is attributed to microsomal hepatic enzymes and primarily consists of oxidation of the imidazole ring, degradation of the oxidized imidazole, oxidative O-dealkylation, oxidative degradation of the piperazine ring, and aromatic hydroxylation (Gascoigne et al., 1981; Heel et al., 1982; Hume and Kerkering 1983; Daneshmend and Warnock, 1988). However, these statements are not backed up with newer data or more advanced approaches and have been haunting the literature ever since, as already stated by others (Whitehouse et al., 1994a). Even more recent data “revisiting” ketoconazole metabolism did not clarify the main pathway, since only metabolites generated in vitro with human liver microsomes or hepatocytes were investigated (Fitch et al., 2009; Kim et al., 2017).
Arylacetamide deacetylase knockout mice are sensitive to ketoconazole-induced hepatotoxicity and adrenal insufficiency
2022, Biochemical PharmacologyDetection of nanocarrier potentiation on drug induced phospholipidosis in cultured cells and primary hepatocyte spheroids by high content imaging and analysis
2018, Toxicology and Applied PharmacologyPredicting in vivo phospholipidosis-inducing potential of drugs by a combined high content screening and in silico modelling approach
2015, Toxicology in VitroCitation Excerpt :In the cell based assays the testable top concentration of ketoconazole was limited with due to cytotoxicity at 200 μM. The PLD observed in vivo by ketoconazole has been suggested to be due to its major metabolite de-N-acetyl ketoconazole (Whitehouse et al., 1994), the formation of this metabolite could be CYP- or flavin-containing monooxygenase (FMO)-mediated (Rodriguez et al., 1999). Indicating that metabolite formation in HepG2 cells requires longer than 1 h to be present in sufficient quantities to show lysosomal trapping and is thus only observed in the PLD assay over a 72 h time period, ketoconazole has previously been shown to be positive using a panel of mRNA markers in HepG2 cells with asparagine synthetase (ASNS) being up-regulated by greater than three-fold, in a test set of 12 known PLD compounds (Sawada et al., 2005).
Immunohistochemistry of LAMP-2 and adipophilin for phospholipidosis in liver and kidney in ketoconazole-treated mice
2013, Experimental and Toxicologic PathologyCitation Excerpt :Ketoconazole, an antifungal agent, induces hepatic phospholipidosis in mice and rats (Hirode et al., 2008; Whitehouse et al., 1994). Ketoconazole is converted to a number of metabolites by hepatic microsomes, and a major metabolite, de-N-acetyl ketoconazole, in mice, is considered to be responsible for ketoconazole-induced phospholipidosis (Whitehouse et al., 1994). In this study, foamy vacuoles appeared in hepatocytes and proximal tubular epithelial cells in ketoconazole-treated mice under fasted conditions, and lipid-like vacuoles were also observed in the hepatocytes.
Comparison of a genomic and a multiplex cell imaging approach for the detection of phospholipidosis
2011, Toxicology in Vitro