Hasinoff B B
Faculty of Pharmacy, University of Manitoba, Winnipeg, Canada.
J Pharm Sci. 1994 Jan;83(1):64-7. doi: 10.1002/jps.2600830115.
The hydrolysis of the cardioprotective agent ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] to its presumed active form under conditions of physiologic pH and temperature were followed by HPLC chromatography. Successful chromatography of all of the hydrolysis products required the use of EDTA in the aqueous eluant to prevent metals in the HPLC flow system from binding to the strongly metal ion-binding product ADR-925. The kinetics of the hydrolysis was followed to approximately 200 h. The ring closest to the methyl group on ICRF-187 was observed to open at about twice the rate of the other ring. This product accumulates in the reaction mixture not only because it is produced more quickly but also because it decays more slowly. ICRF-187 is lost from the reaction mixture with a half-life of 9.3 h, whereas the final hydrolysis product ADR-925 is produced with a half-life of 23.0 h. Rate constants for ring opening to one-ring and two-ring opened hydrolysis products were obtained with a reaction scheme that assumed parallel and consecutive first-order reactions for these steps.
在生理pH值和温度条件下，采用高效液相色谱法跟踪心脏保护剂ICRF - 187 [（+）-1,2 - 双（3,5 - 二氧代哌嗪基-1 - 基）丙烷]水解为其假定活性形式的过程。要成功分离所有水解产物，需要在水性洗脱液中使用乙二胺四乙酸（EDTA），以防止高效液相色谱流动系统中的金属与强金属离子结合产物ADR - 925结合。跟踪水解动力学约200小时。观察到ICRF - 187上最靠近甲基的环的开环速率约为另一个环的两倍。该产物在反应混合物中积累，不仅是因为它产生得更快，还因为它衰变得更慢。ICRF - 187从反应混合物中消失的半衰期为9.3小时，而最终水解产物ADR - 925的产生半衰期为23.0小时。通过一个反应方案获得了开环生成单环和双环开环水解产物的速率常数，该方案假设这些步骤为平行和连续的一级反应。
