PT  - JOURNAL ARTICLE
AU  - B B Hasinoff
TI  - Enzymatic ring-opening reactions of the chiral cardioprotective agent (+) (S)-ICRF-187 and its (-) (R)-enantiomer ICRF-186 by dihydropyrimidine amidohydrolase.
DP  - 1993 Sep 01
TA  - Drug Metabolism and Disposition
PG  - 883--888
VI  - 21
IP  - 5
4099  - http://dmd.aspetjournals.org/content/21/5/883.short
4100  - http://dmd.aspetjournals.org/content/21/5/883.full
SO  - Drug Metab Dispos1993 Sep 01; 21
AB  - 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.