Abstract
The kinetics of the ring-opening reaction of the cardioprotective agent (+) (S)-ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane, dexrazoxane] and its (-) (R)-analog ICRF-186 by the enzyme dihydropyrimidine amidohydrolase (DHPase) has been studied by HLLC. Chromatographic separation of the two single-ring opened hydrolysis products allowed an estimation of the Michaelis parameters for the opening of each individual ring on the two optical isomers. Under nonsaturating conditions, DHPase acts on ICRF-187 4 times faster than it does on ICRF-186. However, the single-ring opened hydrolysis products of both ICRF-187 and ICRF-186 are not substrates of DHPase. Because the active form of ICRF-187 is thought to be its rings-opened metal ion chelating form, these results suggest that DHPase-catalyzed hydrolysis occurring in the liver and the kidney may lead to differences in the pharmacological action and effectiveness of these two optical isomers.
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