TY - JOUR T1 - Relative Plasma Levels of the Cardioprotective Drug Dexrazoxane and Its Two Active Ring-Opened Metabolites in the Rat JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 265 LP - 268 VL - 27 IS - 2 AU - Brian B. Hasinoff AU - Ronald G. Aoyama Y1 - 1999/02/01 UR - http://dmd.aspetjournals.org/content/27/2/265.abstract N2 - 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 intermediates and its fully rings opened hydrolysis product ADR-925. Little is known of the in vivo metabolism of dexrazoxane to its one-ring open intermediates, which may be two of the active forms of dexrazoxane. The one-ring open intermediates were detected within 5 min of i.v. administration of dexrazoxane to rats, suggesting that dexrazoxane is rapidly metabolized in vivo. The plasma concentrations of the one-ring open intermediates varied from 4 to 9% and 6 to 24% of the dexrazoxane concentrations at 5 and 120 min, respectively. The relatively small changes in the levels of the one-ring open intermediates with time suggest that a dynamic steady state is occurring. The ratio of the concentrations of the two one-ring open intermediates was similar to that previously seen for the in vitro dihydropyrimidine amidohydrolase-catalyzed hydrolysis of dexrazoxane. These results are consistent with the hypothesis that dihydropyrimidine amidohydrolase in the liver and kidney is responsible for the metabolism of dexrazoxane in the rat. The American Society for Pharmacology and Experimental Therapeutics ER -