The doxorubicin-cardioprotective drug dexrazoxane undergoes metabolism in the rat to its metal ion-chelating form ADR-925.
OBJECTIVE
Dexrazoxane is clinically used as a doxorubicin-cardioprotective agent and may act by preventing iron-based oxygen free-radical damage through the iron-chelating ability of ADR-925. The metabolism of dexrazoxane (ICRF-187) to its one-ring open hydrolysis products and its rings-opened metal-chelating product ADR-925 was determined in a rat model in order to identify the mechanism by which dexrazoxane acts.


METHODS
A new fluorescence detection flow injection assay utilizing the metal-chelating dye calcein was developed to detect ADR-925 in blood plasma. Dexrazoxane and its one-ring open metabolites were determined by HPLC.


RESULTS
ADR-925 was detected within 5 min of i.v. administration of dexrazoxane to rats, suggesting that dexrazoxane is rapidly metabolized in vivo. The plasma concentrations of ADR-925 exceeded those of both one-ring open intermediates at 30 min and those of dexrazoxane by 80 min and reached a maximum at 80 min, and then slowly decreased.


CONCLUSIONS
The rapid appearance of ADR-925 in plasma may make ADR-925 available to be taken up by heart tissue and bind free iron. These results indicate that the one-ring open dexrazoxane intermediates are enzymatically metabolized to ADR-925 and provide a pharmacodynamic basis for the antioxidant cardioprotective activity of dexrazoxane.
Schroeder
Patricia E
PE
Faculty of Pharmacy, 50 Sifton Road, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada.
Hasinoff
Brian B
BB
D000818:Animals; D001711:Biotransformation; D002317:Cardiovascular Agents / Q000493:pharmacokinetics*; D002614:Chelating Agents; D002851:Chromatography, High Pressure Liquid; D005029:Ethylenediamines / Q000378:metabolism*; D005452:Fluoresceins / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism*; D006207:Half-Life; D007202:Indicators and Reagents / Q000378:metabolism; D007262:Infusions, Intravenous; D007501:Iron / Q000378:metabolism*; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D011929:Razoxane / Q000493:pharmacokinetics*
D002317:Cardiovascular Agents; D002614:Chelating Agents; D005029:Ethylenediamines; D005452:Fluoresceins; D007202:Indicators and Reagents; D011929:Razoxane; C059866:ICRF 198; D007501:Iron; D005998:Glycine; C007740:fluorexon