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

• Published in: Drug metabolism and disposition Vol. 33; no. 6; pp. 719 - 725
• Main Authors: SCHROEDER, Patricia E, WANG, Gu-Qi, BURCZYNSKI, Frank J, HASINOFF, Brian B
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01-06-2005
• Subjects: Adult; Animals; Biological and medical sciences; Cardiotonic Agents - blood; Cardiotonic Agents - chemistry; Cardiotonic Agents - metabolism; Cardiovascular system; Female; Hepatocytes - metabolism; Humans; Medical sciences; Miscellaneous; Myocytes, Cardiac - metabolism; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Razoxane - blood; Razoxane - chemistry; Razoxane - metabolism; Drug; Biological fluid; Rat; Metabolite; Rodentia; Cardioprotective agent; Dexrazoxane; Metabolism; In vitro; Blood; Myocyte; Vertebrata; Mammalia; Animal; Chelating agent; Piperazine derivatives; Pharmacokinetics
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.104.003186

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 ′-[(1 S )-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 Ca 2+ and Mg 2+ 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.