cardiovascular-agents and fluorexon

Dexrazoxane is a cardioprotective antioxidant that is clinically used to reduce the cardiotoxicity of the chemotherapeutic drug doxorubicin. We examined the hypothesis that dexrazoxane also may be able to protect neonatal rat cardiac myocytes from hypoxia-reoxygenation damage. Hypoxia-reoxygenation damage is thought to involve oxidative stress on the heart muscle, possibly by the production of hydroxyl radicals mediated by iron. The results of this study showed that dexrazoxane was highly effective in protecting myocytes from hypoxia-reoxygenation-induced lactate dehydrogenase release. The metal chelating hydrolysis product of dexrazoxane, ADR-925, also protected myocytes from hypoxia-reoxygenation damage, although it was less effective than dexrazoxane. This study also showed that ADR-925 and dexrazoxane rapidly entered myocytes and displaced iron from a fluorescence-quenched trapped intracellular iron-calcein complex. These results suggest that dexrazoxane may protect myocytes against hypoxia-reoxygenation-induced damage by chelating free or loosely bound iron, thus preventing site-specific iron-based oxygen radical damage. Thus, dexrazoxane or its analogs may have some clinical utility in preventing tissue damage that occurs after a stroke or heart attack.

Topics: Animals; Cardiovascular Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Ethylenediamines; Extracorporeal Membrane Oxygenation; Fluoresceins; Fluorescent Dyes; Glycine; Hypoxia; Ion Transport; L-Lactate Dehydrogenase; Models, Cardiovascular; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Razoxane; Time Factors; Treatment Failure

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.. 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.. 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.. 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.

Topics: Animals; Biotransformation; Cardiovascular Agents; Chelating Agents; Chromatography, High Pressure Liquid; Ethylenediamines; Fluoresceins; Glycine; Half-Life; Indicators and Reagents; Infusions, Intravenous; Iron; Male; Molecular Structure; Rats; Rats, Sprague-Dawley; Razoxane