Tsuzuki N, Hama T, Kawada M, Hasui A, Konishi R, Shiwa S, Ochi Y, Futaki S, Kitagawa K
Telkoku Seiyaku Company Ltd., Kagawa, Japan.
J Pharm Sci. 1994 Apr;83(4):481-4. doi: 10.1002/jps.2600830407.
Five AZT (azidothymidine) prodrugs conjugated with the 1-adamantane moiety via an ester bond were synthesized to improve the transport of AZT into the central nervous system (CNS). In in vitro degradation studies with rat and human plasma, it was demonstrated that the prodrugs were degraded enzymatically and converted quantitatively to their parent drug. AZT. As assessed by octanol-buffer partitioning, the prodrugs were much more lipophilic than AZT and were expected to penetrate the blood-brain barrier (BBB) readily. In in vivo studies, in which the prodrugs were administered intravenously to rat, the prodrugs in brain tissue were detected at 7-18 times higher concentrations than AZT in spite of the negligible amount of the prodrug in the cerebrospinal fluid. These results indicate that the introduction to AZT of the 1-adamantane moiety results in the enhancement of the BBB penetration. This pharmaceutical approach would be beneficial for the efficient treatment of the CNS infection by human immunodeficiency virus.
合成了五种通过酯键与1-金刚烷部分共轭的齐多夫定（AZT）前药，以改善AZT向中枢神经系统（CNS）的转运。在大鼠和人血浆的体外降解研究中，证明这些前药被酶促降解并定量转化为其母体药物AZT。通过正辛醇-缓冲液分配评估，这些前药比AZT亲脂性强得多，预计能轻易穿透血脑屏障（BBB）。在体内研究中，将前药静脉注射给大鼠，尽管脑脊液中的前药含量可忽略不计，但脑组织中的前药浓度比AZT高7至18倍。这些结果表明，在AZT中引入1-金刚烷部分可增强血脑屏障的穿透性。这种制药方法将有利于有效治疗人类免疫缺陷病毒引起的中枢神经系统感染。
