The dihydroorotase inhibitor 5-aminoorotic acid inhibits the metabolism in the rat of the cardioprotective drug dexrazoxane and its one-ring open metabolites.
Dexrazoxane (ICRF-187) is clinically used as a doxorubicin cardioprotective agent and to prevent anthracycline extravasation injury. It may act by preventing iron-based oxygen free radical damage through the iron-chelating ability of its metabolite N,N'-[(1S)-1-methyl-1,2-ethanediyl]bis[(N-(2-amino-2-oxoethyl)]glycine (ADR-925). Dexrazoxane undergoes an initial metabolism to its two one-ring open intermediates [N-(2-amino-2-oxoethyl)-N-[(1S)-2-(3,5-dioxo-1-piperazinyl)-1-methylethyl]glycine (B) and N-(2-amino-2-oxoethyl)-N-[(2S)-2-(3,5-dioxo-1-piperazinyl)propyl]glycine (C)] and is then further metabolized to its presumably active metal-chelating form ADR-925. We previously showed that the first ring opening reaction is catalyzed by dihydropyrimidinase and the second by dihydroorotase (DHOase), but not vice versa. To determine whether DHOase was important in the metabolism of dexrazoxane, its metabolism and that of B and C to ADR-925 were measured in rats that were pretreated with the DHOase inhibitor 5-aminoorotic acid. In rats pretreated with 5-aminoorotic acid the area-under-the-curve concentration of ADR-925 was reduced 5.3-fold. In rats treated with a mixture of B and C, the maximum concentration of ADR-925 in the plasma was significantly decreased in rats pretreated with 5-aminoorotic acid, which indicates that DHOase directly metabolized B and C. Both heart and liver tissue levels of ADR-925 in rats were also greatly reduced by pretreatment with 5-aminoorotic acid. Together these results indicate that the metabolism of dexrazoxane and of B and C is mediated by DHOase. These results provide a mechanistic basis for the antioxidant cardioprotective activity of dexrazoxane.
Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada.
Patricia E
PE
Schroeder
Daywin
D
Patel
Brian B
BB
Hasinoff
D000818:Animals; D002316:Cardiotonic Agents / Q000493:pharmacokinetics*; D004080:Dihydroorotase / Q000037:antagonists & inhibitors*; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D006868:Hydrolysis; D008297:Male; D009206:Myocardium / Q000201:enzymology; D009963:Orotic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011929:Razoxane / Q000493:pharmacokinetics*
D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D011929:Razoxane; D009963:Orotic Acid; D004317:Doxorubicin; D004080:Dihydroorotase; C532756:5-aminoorotic acid