Key result
In vitro amrubicin and amrubicinol metabolism relies on specific reductases and is unaffected by cisplatin.
Why the study?
The enzymatic pathways involved in the in vitro metabolism of amrubicin and its active metabolite amrubicinol in rat and human liver microsomes and cytosol were not fully characterized.
What enzymes mediate the in vitro metabolism of amrubicin and amrubicinol in rat and human liver microsomes and cytosol?
What enzymes mediate the in vitro metabolism of amrubicin and amrubicinol in rat and human liver microsomes and cytosol?
The study identifies the specific enzymes responsible for the in vitro metabolism of amrubicin and its active metabolite amrubicinol, noting no metabolic interaction with cisplatin.
Identifies amrubicin reductases in vitro without cisplatin interaction; leaves open in vivo relevance and clinical translation.
The in vitro metabolism of amrubicin by rat and human liver microsomes and cytosol was examined. The main metabolic routes in both species were reductive deglycosylation and carbonyl group reduction in the side-chain. In vitro metabolism of amrubicinol by rat and human liver microsomes and cytosol was also examined and the main metabolic route of this active metabolite was reductive deglycosylation. Metabolism of amrubicin in human liver microsomes was inhibited by TlCl(3) and that in human liver cytosol was inhibited by dicumarol and quercetin. Generation of amrubicinol was inhibited only by quercetin. The results indicate that metabolism of amrubicin is mediated by NADPH-cytochrome P450 reductase, NADPH:quinone oxidoreductase and carbonyl reductase. In addition, generation of amrubicinol is mediated by carbonyl reductase. Metabolism of amrubicinol in human liver microsomes was inhibited by TlCl(3) and that in human liver cytosol was inhibited by dicumarol. The results indicate that metabolism of amrubicinol is mediated by NADPH-cytochrome P450 reductase and NADPH:quinone oxidoreductase. To investigate the influence of cisplatin on the metabolism of amrubicin and amrubicinol, human liver microsomes and cytosol were pre-incubated with cisplatin. This did not change the rates of amrubicin and amrubicinol metabolism in either human liver microsomes or cytosol.
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Tani et al. (2005) studied this question. Amrubicin and amrubicinol was evaluated on In vitro metabolism routes and enzymes involved. In vitro metabolism of amrubicin and amrubicinol is mediated by NADPH-cytochrome P450 reductase, NADPH:quinone oxidoreductase, and carbonyl reductase, and is not altered by cisplatin.
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