Metabolism of the one-ring open metabolites of the cardioprotective drug dexrazoxane to its active metal-chelating form in the rat.
Dexrazoxane (ICRF-187) 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 its fully hydrolyzed metabolite ADR-925 (N,N'-[(1S)-1-methyl-1,2-ethanediyl]-bis[(N-(2-amino-2-oxoethyl)]glycine). Dexrazoxane undergoes initial metabolism to its two one-ring open intermediates and is then further metabolized to its active metal ion-binding form ADR-925. The metabolism of these intermediates to the ring-opened metal-chelating product ADR-925 has been determined in a rat model to identify the mechanism by which dexrazoxane is activated. The plasma concentrations of both intermediates rapidly decreased after their i.v. administration to rats. A maximum concentration of ADR-925 was detected 2 min after i.v. bolus administration, indicating that these intermediates were both rapidly metabolized in vivo to ADR-925. The kinetics of the initial appearance of ADR-925 was consistent with formation rate-limited metabolism of the intermediates. After administration of dexrazoxane or its two intermediates, ADR-925 was detected in significant levels in both heart and liver tissue but was undetectable in brain tissue. The rapid rate of metabolism of the intermediates was consistent with their hydrolysis by tissue dihydroorotase. 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 studies showed that the two one-ring open metabolites of dexrazoxane were rapidly metabolized in the rat to ADR-925, and thus, these results provide a mechanism by which dexrazoxane is activated to its active metal-binding form.
Schroeder
Patricia E
PE
Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba R3T 2N2 Canada.
Hasinoff
Brian B
BB
D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002316:Cardiotonic Agents / Q000493:pharmacokinetics*; D002614:Chelating Agents / Q000032:analysis / Q000493:pharmacokinetics; D004080:Dihydroorotase / Q000378:metabolism; D005029:Ethylenediamines / Q000097:blood* / Q000493:pharmacokinetics; D005998:Glycine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011929:Razoxane / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*
D002316:Cardiotonic Agents; D002614:Chelating Agents; D005029:Ethylenediamines; C509140:N-(2-amino-2-oxoethyl)-N-(2-(3,5-dioxo-1-piperazinyl)-1-methylethyl)glycine; C509141:N-(2-amino-2-oxoethyl)-N-(2-(3,5-dioxo-1-piperazinyl)propyl)glycine; D011929:Razoxane; C059866:ICRF 198; D000581:Amidohydrolases; C020047:dihydropyrimidinase; D004080:Dihydroorotase; D005998:Glycine