Metabolism of the one-ring open metabolites of the cardioprotective drug dexrazoxane to its active metal-chelating form in the rat.
نویسندگان
چکیده
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.
منابع مشابه
Dmd #5546 -1- Metabolism of the One-ring Open Metabolites of the Cardioprotective Drug Dexrazoxane to Its Active Metal Chelating Form in the Rat
متن کامل
Relative plasma levels of the cardioprotective drug dexrazoxane and its two active ring-opened metabolites in the rat.
A postcolumn derivatization reversed-phase high-pressure liquid chromatography method has been developed to detect and separate the one-ring open intermediates of dexrazoxane (ICRF-187) in blood plasma. 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 its one-ring open int...
متن کاملMetabolism of the cardioprotective drug dexrazoxane and one of its metabolites by isolated rat myocytes, hepatocytes, and blood.
The metabolism of the antioxidant cardioprotective agent dexrazoxane (ICRF-187) and one of its one-ring open metabolites to its active metal ion binding form N,N'-[(1S)-1-methyl-1,2-ethanediyl-]bis[(N-(2-amino-2-oxoethyl)]glycine (ADR-925) has been investigated in neonatal rat myocyte and adult rat hepatocyte suspensions, and in human and rat blood and plasma with a view to characterizing their...
متن کاملThe dihydroorotase inhibitor 5-aminoorotic acid inhibits the metabolism in the rat of the cardioprotective drug dexrazoxane and its one-ring open metabolites.
Dexrazoxane (ICRF-187) is clinically used as a doxorubicin cardioprotective agent and to prevent anthracycline extravasation injury. It may act by preventing iron-based oxygen free radical damage through the iron-chelating ability of its metabolite N,N'-[(1S)-1-methyl-1,2-ethanediyl]bis[(N-(2-amino-2-oxoethyl)]glycine (ADR-925). Dexrazoxane undergoes an initial metabolism to its two one-ring op...
متن کاملThe metabolites of the cardioprotective drug dexrazoxane do not protect myocytes from doxorubicin-induced cytotoxicity.
The clinically approved cardioprotective agent dexrazoxane (ICRF-187) and two of its hydrolyzed metabolites (a one-ring open form of dexrazoxane and ADR-925) were examined for their ability to protect neonatal rat cardiac myocytes from doxorubicin-induced damage. Dexrazoxane may protect against doxorubicin-induced damage to myocytes through its strongly metal-chelating hydrolysis product ADR-92...
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عنوان ژورنال:
- Drug metabolism and disposition: the biological fate of chemicals
دوره 33 9 شماره
صفحات -
تاریخ انتشار 2005