Stereoselective metabolism of dexrazoxane (ICRF-187) and levrazoxane (ICRF-186)

A chiral HPLC method has been developed to separate razoxane (ICRF-159) in blood plasma into its enantiomers dexrazoxane (ICRF-187) and levrazoxane (ICRF-186). Dexrazoxane is clinically used as a doxorubicin cardioprotective agent and little is known of its in vivo metabolism. After intravenous administration of 20 mg/kg of razoxane to rats, the razoxane was eliminated from the plasma with a half-time of approximately 20 min. The levrazoxane:dexrazoxane ratio continuously increased with time to a value of 1.5 at 150 min, indicating that dexrazoxane is metabolized faster than levrazoxane. These results, confirmed with studies on liver supernatants, are consistent with the hypothesis that dihydropyrimidine amidohydrolase in the liver and kidney is responsible for the preferential metabolism of dexrazoxane in the rat compared to levrazoxane. It is possible that on a dose-per-dose basis marginally higher therapeutic levels of levrazoxane might be achieved in the heart tissue for a longer time compared to dexrazoxane due to dihydropyrimidine amidohydrolase-based metabolism in the liver and kidney. However, given the relatively small difference in elimination of the two enantiomers, it would be difficult to predict from this study whether or not dexrazoxane or levrazoxane might be more efficacious in reducing cardiotoxicity.