Characterization of the enzymes involved in the in vitro metabolism of amrubicin hydrochloride.
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.
Tani
N
N
Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd, Osaka, Japan. tanin1@sc.sumitomochem.co.jp
Yabuki
M
M
Komuro
S
S
Kanamaru
H
H
D000328:Adult; D000368:Aged; D000818:Animals; D018943:Anthracyclines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002945:Cisplatin / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008875:Middle Aged; D008954:Models, Biological; D051381:Rats; D013997:Time Factors
D018943:Anthracyclines; D004791:Enzyme Inhibitors; C116173:amrubicinol; C055866:amrubicin; D002945:Cisplatin