Metabolism of the cardioprotective drug dexrazoxane and one of its metabolites by isolated rat myocytes, hepatocytes, and blood.
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.
Schroeder
Patricia E
PE
Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada.
Wang
Gu-Qi
GQ
Burczynski
Frank J
FJ
Hasinoff
Brian B
BB
D000328:Adult; D000818:Animals; D002316:Cardiotonic Agents / Q000097:blood* / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011929:Razoxane / Q000097:blood* / Q000737:chemistry / Q000378:metabolism*
D002316:Cardiotonic Agents; D011929:Razoxane