TY - JOUR T1 - METABOLISM OF THE CARDIOPROTECTIVE DRUG DEXRAZOXANE AND ONE OF ITS METABOLITES BY ISOLATED RAT MYOCYTES, HEPATOCYTES, AND BLOOD JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 719 LP - 725 DO - 10.1124/dmd.104.003186 VL - 33 IS - 6 AU - Patricia E. Schroeder AU - Gu-Qi Wang AU - Frank J. Burczynski AU - Brian B. Hasinoff Y1 - 2005/06/01 UR - http://dmd.aspetjournals.org/content/33/6/719.abstract N2 - 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 hydrolysis-activation. Dexrazoxane is clinically used to reduce the iron-based oxygen free radical-mediated cardiotoxicity of the anticancer drug doxorubicin. Dexrazoxane may act through its hydrolysis product ADR-925 by removing iron from the iron-doxorubicin complex, or binding free iron, thus preventing oxygen radical formation. Our results indicate that dexrazoxane underwent partial uptake and/or hydrolysis by myocytes. A one-ring open metabolite of dexrazoxane underwent nearly complete dihydroorotase-catalyzed metabolism in a myocyte suspension. Hepatocytes that contain both dihydropyrimidinase and dihydroorotase completely hydrolyzed dexrazoxane to ADR-925 and released it into the extracellular medium. Thus, in hepatocytes, the two liver enzymes acted in concert, and sequentially, on dexrazoxane, first to produce the two ring-opened metabolites, and then to produce the metabolite ADR-925. We also showed that the hydrolysis of one of these metabolites was promoted by Ca2+ and Mg2+ in plasma, and thus, further metabolism of these intermediates likely occurs in the plasma after they are released from the liver and kidney. In conclusion, these studies provide a nearly complete description of the metabolism of dexrazoxane by myocytes and hepatocytes to its presumably active form, ADR-925. The American Society for Pharmacology and Experimental Therapeutics ER -