Brain and CSF specific chemical delivery systems for beta-lactam antibiotics. Study of two dihydropyridine derivatives of benzylpenicillin in rabbits and dogs.

Drug design and delivery Pub Date : 1990-12-01
W M Wu, E Pop, E Shek, R Clemmons, N Bodor
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Abstract

Following previous studies in rats, the ability of two chemical delivery systems (CDSs) to deliver benzyl penicillin (1) to the central nervous system of rabbits and dogs was investigated. One of the systems (3) was a diester of methylene diol, and the other (5) a diester of ethylene 1,2-diol; in both, one hydroxyl group of the diol was esterified by the 3-carboxylic acid group of benzylpenicillin, and the other by the carboxy group of an N-methyldihydropyridine (dihydrotrigonelline). The basis of the system is the ability of the dihydropyridine components to undergo oxidation to quaternary pyridinium salts (2 from 3, and 4 from 5). In vitro relative stability studies were first performed in 10% rabbit brain homogenate, rabbit CSF and dog CSF. The results showed that the CDSs (3 and 5) were more stable than the corresponding quaternary salts (2 and 4). Hydrolysis of 2 and 3 resulted in the release of 1, whereas hydrolysis of 4 and 5 released both 1 and the hydroxyethyl ester (6) of 1. In vivo distribution studies were performed in rabbits and dogs. After i.v. administration of equimolar doses of 1 or the CDSs, levels of 1 in brain and CSF were substantially higher and more prolonged in the cases of the CDSs than in the case of 1 itself. Brain levels of 1 were lower following administration of 5, as compared with 3, due to the release of the intermediate compound, the hydroxyethyl ester (6) of 1, which was not hydrolyzed efficiently to 1 in rabbit or dog brain. The substantially increased and prolonged penicillin levels following administration of the CDSs arise as the result of improved penetration of the lipophilic CDSs across the blood-brain barrier, and a "lock-in" effect of the corresponding quaternary salts generated in situ.

-内酰胺类抗生素的脑和脑脊液特异性化学传递系统。青霉素两种二氢吡啶衍生物在家兔和狗体内的研究。
继之前的大鼠研究之后,我们研究了两种化学传递系统(CDSs)将苄青霉素(1)传递到兔子和狗的中枢神经系统的能力。其中一个体系(3)是亚甲基二醇的二酯,另一个体系(5)是乙烯1,2-二醇的二酯;在这两种化合物中,二醇的一个羟基被青霉素的3-羧基酯化,另一个羟基被n -甲基二氢吡啶(二氢葫芦巴碱)的羧基酯化。该系统的基础是二氢吡啶组分氧化成季吡啶盐的能力(2从3,4从5)。首先在10%的兔脑匀浆、兔脑脊液和狗脑脊液中进行了体外相对稳定性研究。结果表明,CDSs(3和5)比相应的季盐(2和4)更稳定。2和3的水解会释放1,而4和5的水解会释放1和1的羟乙基酯(6)。在家兔和狗体内进行了分布研究。在静脉注射等量剂量的1或CDSs后,CDSs患者脑和脑脊液中的1水平明显高于1本身,且持续时间更长。与3相比,5的脑内1的水平较低,这是由于中间化合物1的羟乙基酯(6)的释放,在兔或狗的脑内不能有效地水解为1。由于亲脂性CDSs穿透血脑屏障的能力增强,以及相应的季盐在原位产生的“锁定”效应,在给药CDSs后青霉素水平大幅增加和延长。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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