Received for publication November 30, 2004.
Revised March 3, 2005.
Accepted for publication March 3, 2005.

METABOLISM OF THE CARDIOPROTECTIVE DRUG DEXRAZOXANE AND ONE OF ITS METABOLITES BY ISOLATED RAT MYOCYTES, HEPATOCYTES AND BY BLOOD

Abstract

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 ADR-925 have 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, to first 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.

Key words: anticancer agents, antioxidants, cardiac toxicity, isolated hepatocytes, metabolite identification, oxidative stress, reactive oxygen species

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