Comparative metabolism and pharmacokinetics of doxorubicin and 4'-epidoxorubicin in plasma, heart and tumor of tumor-bearing mice.
Epidoxorubicin, a stereoisomer of doxorubicin, shows comparable antitumor activity but diminished cardiotoxicity compared with the latter. To find a pharmacokinetic basis for the observed difference in cardiotoxicity between the drugs, concentrations of doxorubicin, epidoxorubicin and all known metabolites were measured in the plasma, heart and tumor tissue of BALB/c mice bearing colon-26 tumors. Both drugs were injected at the same dose (10 mg/kg) as an i.v. bolus. Plasma, heart and tumor samples were obtained from two mice sacrificed at regular intervals over 48 h. Plasma and tissue extracts were analyzed by HPLC with fluorescence detection. The parent compounds and the two 7d-aglycones were present in all three compartments, whereas doxorubicinol (Aol) and epidoxorubicinol (Eol) could only be detected in the plasma and heart. Half-lives and AUCs of doxorubicin and its metabolites were higher than the corresponding values for epidoxorubicin and its metabolites in all three compartments.
van der Vijgh
W J
WJ
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
Maessen
P A
PA
Pinedo
H M
HM
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000378:metabolism*; D004317:Doxorubicin / Q000097:blood / Q000493:pharmacokinetics*; D015251:Epirubicin / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000378:metabolism*
D015251:Epirubicin; D004317:Doxorubicin