Identification of the Metabolites of the Antioxidant Flavonoid 7-Mono-O-(β-hydroxyethyl)-rutoside in Mice

The clinical use of the anticancer drug doxorubicin is limited by severe cardiotoxicity. In mice, the semisynthetic antioxidant flavonoid 7-mono-O-(beta-hydroxyethyl)-rutoside (monoHER) has been successfully used as a protector against doxorubicin-induced cardiotoxicity. However, most monoHER has already been cleared from the body at the time that doxorubicin concentrations are still high. This result suggests that not only the parent compound monoHER itself but also monoHER metabolites could be responsible for the observed cardioprotective effects in mice. Therefore, in the present study, we investigated the metabolism of monoHER in mice. Mice were administered 500 mg/kg monoHER intraperitoneally. At different time points after monoHER administration, bile was collected and analyzed for the presence of monoHER metabolites. The formed metabolites were identified by liquid chromatography-diode array detection-time of flight-mass spectrometry. Thirteen different metabolites were identified. The observed routes of monoHER metabolism are methylation, glucuronidation, oxidation of its hydroxyethyl group, GSH conjugation, and hydrolysis of its disaccharide. In line with other flavonoids, methylated monoHER and the monoHER glucosides are expected to have relatively high cellular uptake and low clearance from the body. Therefore, these metabolites might contribute to the observed protection of monoHER against doxorubicin-induced cardiotoxicity.