Metabolism of 4'-modified analogs of doxorubicin. unique glucuronidation pathway for 4'-epidoxorubicin

Eur J Cancer Clin Oncol. 1984 Jul;20(7):919-26. doi: 10.1016/0277-5379(84)90165-2.


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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / metabolism*
  • Antibiotics, Antineoplastic / urine
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / urine
  • Chromatography, High Pressure Liquid
  • Doxorubicin / analogs & derivatives
  • Doxorubicin / metabolism*
  • Doxorubicin / urine
  • Epirubicin
  • Glucuronates / metabolism*
  • Glucuronates / urine
  • Humans
  • In Vitro Techniques
  • Liver / metabolism
  • Male
  • Rats
  • Rats, Inbred Strains


  • Antibiotics, Antineoplastic
  • Antineoplastic Agents
  • Glucuronates
  • Epirubicin
  • Doxorubicin
  • esorubicin