Buur A, Bundgaard H
Royal Danish School of Pharmacy, Department of Pharmaceutical Chemistry, Copenhagen.
Acta Pharm Nord. 1991;3(1):51-6.
Bioreversible derivatization of cimetidine to afford more lipophilic prodrugs was performed by N-acyloxymethylation of its imidazole group as well as by N-acylation with various chloroformates. Both the N-acyloxymethyl and N-alkoxycarbonyl derivatives were readily hydrolyzed to cimetidine in human plasma and in rat liver homogenate. The pH-rate profiles for the hydrolysis of the derivatives were derived at 60 degrees C. The derivatives were all more lipophilic than the parent drug as determined by partition experiments in octanol-aqueous buffer systems. In vitro studies using the modified Ussing-chamber technique showed that some derivatives possessed increased permeability coefficients for the transport across the rat jejunum relative to cimetidine. The results obtained suggest that these derivatives may be useful to improve the biomembrane transport characteristics of the hydrophilic cimetidine.
通过西咪替丁咪唑基团的N-酰氧基甲基化以及与各种氯甲酸酯的N-酰化反应，对其进行生物可逆衍生化以得到亲脂性更强的前药。N-酰氧基甲基衍生物和N-烷氧羰基衍生物在人血浆和大鼠肝匀浆中均能迅速水解为西咪替丁。在60℃下得出了衍生物水解的pH-速率曲线。通过在辛醇-水缓冲液系统中的分配实验确定，所有衍生物都比母体药物更具亲脂性。使用改良的Ussing扩散池技术进行的体外研究表明，相对于西咪替丁，一些衍生物在跨大鼠空肠转运时具有更高的渗透系数。所得结果表明，这些衍生物可能有助于改善亲水性西咪替丁的生物膜转运特性。
