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 (I CRF-186). Dexrazoxane is clinically used as a doxorubicin cardioprotective agent and little is known of its in vivo metabolism. After intravenous admi nistration of 20 mg/kg of razoxane to rats, the razoxane was eliminated fro m the plasma with a half-time of similar to 20 min. The levrazoxane:dexrazo xane ratio continuously increased with time to a value of 1.5 at 150 min, i ndicating that dexrazoxane is metabolized faster than levrazoxane, These re sults, confirmed with studies on liver supernatants, are consistent with th e hypothesis that dihydropyrimidine amidohydrolase in the liver and kidney is responsible for the preferential metabolism of dexrazoxane in the rat co mpared to levrazoxane. It is possible that on a dose-per-dose basis margina lly 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 woul d be difficult to predict from this study whether or not dexrazoxane or lev razoxane might be more efficacious in reducing cardiotoxicity. Chirality 11 :286-290, 1999, (C) 1999 Wiley-Liss, Inc.