Metabolism of 4'-modified analogs of doxorubicin. unique glucuronidation pathway for 4'-epidoxorubicin.
The metabolism of doxorubicin (A), 4'-epidoxorubicin (E) and 4'-deoxydoxorubicin (D) was studied in vitro by incubating the analogs with rat liver subcellular fractions and in vivo by chromatographic analysis of human urine. Metabolites were identified by high-pressure liquid chromatography, fluorescence spectroscopy and enzymatic conversion. Human urine contained unchanged drug as well as the corresponding alcohol metabolites in all cases; however, urine of patients who received E also contained two glucuronides which could not be detected in the urine of patients who received A or D. We have identified these glucuronides as 4'-epidoxorubicin glucuronide (E-Glu) and 4'-epidoxorubicinol glucuronide (Eol-Glu). It was concluded that the glucuronide moiety is linked to the daunosamine sugar at the C4'-OH position. A hypothesis is proposed that this glucuronidation pathway may explain the differences in pharmacokinetics and toxicity between E and A. Rat liver microsomes were found to convert all three drugs to the 7-deoxyaglycones at the same rate. Rat liver 100,000 g supernatant was found to be capable of converting these drugs to their respective alcohol metabolites, doxorubicinol (Aol) being formed somewhat slower than 4'-epidoxorubicinol (Eol) and 4'-deoxydoxorubicinol (Dol).
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism* / Q000652:urine; D000970:Antineoplastic Agents / Q000378:metabolism / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000652:urine; D015251:Epirubicin; D005965:Glucuronates / Q000378:metabolism* / Q000652:urine; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D005965:Glucuronates; D015251:Epirubicin; D004317:Doxorubicin; C030851:esorubicin