Metabolism of 4′-modified analogs of doxorubicin. Unique glucuronidation pathway for 4′-epidoxorubicin

H. Weenen, J. M S Van Maanen, M. M. De Planque, J. G. McVie, H. M. Pinedo

Research output: Contribution to journalArticle

Abstract

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).

Original languageEnglish (US)
Pages (from-to)919-926
Number of pages8
JournalEuropean Journal of Cancer and Clinical Oncology
Volume20
Issue number7
DOIs
StatePublished - 1984
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

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