Murakami T, Shek E, Pop E, Bodor N
University of Florida, Center for Drug Design and Delivery, Gainesville 32610.
J Pharm Sci. 1989 Sep;78(9):732-7. doi: 10.1002/jps.2600780906.
The stability of nine chemical delivery systems (CDSs) for phenytoin (DPH) was studied in aqueous buffers and in biological materials. The systems were based on a dihydropyridine in equilibrium quaternary pyridinium salt redox pair attached to 3-(hydroxymethyl)phenytoin via an ester linkage. The pyridinium derivatives released DPH in aqueous buffers and their hydrolytic reactivity was consistent with their chemical structure. Although in rat blood and plasma all pyridinium esters hydrolyzed rapidly, there was a wide range in the hydrolysis rates in rat brain homogenate. The sterically hindered 1-alkylcarboxynicotinamide was the least reactive ester (t1/2 = 98.2 min), while the trigonellylglycolate ester was the fastest to hydrolyze enzymatically (t1/2 = 2 min) in rat brain homogenate. In acidic media, the major products of all dihydropyridine esters were the corresponding water adducts, the 6-hydroxy- 1,4,5,6-tetrahydropyridines. These adducts were of no significance in biological materials. After comparison of the relative stability of the corresponding pairs of dihydropyridine and pyridinium ion in brain homogenate and the absolute stability of the various dihydropyridines, two CDSs were chosen for further in vivo evaluations. The CDSs chosen were the dihydrotrigonellinate ester and its 6-methyl derivative.
研究了九种苯妥英（DPH）化学传递系统（CDS）在水性缓冲液和生物材料中的稳定性。这些系统基于通过酯键连接到3-（羟甲基）苯妥英上的二氢吡啶处于平衡季铵盐氧化还原对。吡啶鎓衍生物在水性缓冲液中释放DPH，其水解反应性与其化学结构一致。虽然在大鼠血液和血浆中所有吡啶鎓酯都迅速水解，但在大鼠脑匀浆中的水解速率范围很广。空间位阻的1-烷基羧基烟酰胺是反应性最低的酯（t1/2 = 98.2分钟），而在大鼠脑匀浆中，葫芦巴醇酸酯是酶促水解最快的（t1/2 = 2分钟）。在酸性介质中，所有二氢吡啶酯的主要产物是相应的水加合物，即6-羟基-1,4,5,6-四氢吡啶。这些加合物在生物材料中无意义。在比较了脑匀浆中二氢吡啶和吡啶鎓离子相应对的相对稳定性以及各种二氢吡啶的绝对稳定性之后，选择了两种CDS进行进一步的体内评估。选择的CDS是葫芦巴醇酸二氢酯及其6-甲基衍生物。
