Characterization of the enzymes involved in thein vitrometabolism of amrubicin hydrochloride

Abstract

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.

Risk Factors for Predicting Severe Neutropenia Induced by Amrubicin in Patients with Advanced Lung Cancer

“…The in vitro cytotoxic activity of AMR-OH is approximately 10–100 times more potent than that of AMR [2]. AMR and AMR-OH are inactivated mainly by NAD(P)H (quinone oxide reductase and NADPH P-450 reductase) [3]. Then, metabolites are excreted thorough bile.…”

Pharmacokinetic and pharmacodynamic study on amrubicin and amrubicinol in Japanese patients with lung cancer

“…Then, AMR and AMR-OH are inactivated by NAD (P) H: quinone oxide reductase (NQO) and NADPH P-450 reductase [15].…”

Amrubicin as Second-line and Beyond Treatment for Platinum-refractory Advanced Thymic Carcinoma

“…AMR and amrubicinol are inhibitors of DNA topoisomerase II, which exerts a cytotoxic effect by stabilizing a topoisomerase II-mediated cleavable complex, although they may also exert a minority of their effects as a result of DNA intercalation. Amrubicinol is 5 -100 times more active than AMR (10,11). Several reports have demonstrated a high RR to first-line combination chemotherapies involving ADOC and CODE in Japanese patients with advanced TC (4,5).…”

“…Jpn J Clin Oncol 2013;43 (10) 1019 EFFICACY A partial response was confirmed in four patients, stable disease in one patient and progressive disease in four patients, giving a response rate (RR) of 44.4% [exact 95% confidence interval (CI): 13.7 -78.8%, Table 3]. The median OS and the median PFS were 6.4 and 4.9 months, respectively (Fig.…”