Zhang Q, Liang Z, Chen L Y, Sun X, Gong T, Zhang Z R
Sichuan University, Chengdu, People's Republic of China.
Arzneimittelforschung. 2012 Jun;62(6):261-6. doi: 10.1055/s-0032-1306273. Epub 2012 Mar 9.
As a preventive and treatment drug for Alzheimer's disease (AD), naproxen's clinical application is hampered by its limited distribution in the brain. To increase the delivery of naproxen across the blood-brain barrier (BBB), 3 prodrugs (P1, P2 and P3) of naproxen were synthesized through either ester bond or amido bond using the dimethylamino moiety as a brain-targeting ligand. The in vitro release of naproxen from the 3 prodrugs was studied in PBS, rat plasma and brain homogenate. P3 with an amido bond appeared to be highly stable in all incubation media, whereas P1 and P2 with ester bonds were partially hydrolyzed in alkaline environment and brain homogenate to yield the parent drug. After i. v. administration to rats, the brain concentration of total naproxen (summation of released and bound naproxen, TN) of P1, P2 and P3 groups were 28.81, 24.51 and 15.54 times greater than that of the control naproxen group at 5 min, respectively, and the brain AUC0-t were 6.94, 10.06 and 6.70 times greater than that of the control naproxen group. In addition, the Cmax of TN in the brain after the administration of prodrugs with ester bonds (P1 and P2) was higher than that of the amide prodrug (P3). The results highlighted the possibility of brain delivery of naproxen using prodrug strategies based on the brain-targeting ligand with dimethylamino moiety, in which the linkage between drug and targeting group might play an important role in modulating the in vivo behaviors of these prodrugs.
作为一种用于治疗阿尔茨海默病（AD）的预防和治疗药物，萘普生在临床上的应用因在大脑中的分布有限而受到阻碍。为了增加萘普生通过血脑屏障（BBB）的递送，使用二甲基氨基部分作为脑靶向配体，通过酯键或酰胺键合成了3种萘普生前药（P1、P2和P3）。在磷酸盐缓冲液（PBS）、大鼠血浆和脑匀浆中研究了萘普生从这3种前药中的体外释放情况。具有酰胺键的P3在所有孵育介质中似乎都高度稳定，而具有酯键的P1和P2在碱性环境和脑匀浆中部分水解以产生母体药物。给大鼠静脉注射后，P1、P2和P3组的总萘普生（释放的和结合的萘普生总和，TN）的脑浓度在5分钟时分别比对照萘普生组高28.81、24.51和15.54倍，并且脑AUC0-t分别比对照萘普生组高6.94、10.06和6.70倍。此外，给予具有酯键的前药（P1和P2）后，脑中TN的Cmax高于酰胺前药（P3）。结果突出了使用基于具有二甲基氨基部分的脑靶向配体的前药策略将萘普生递送至脑的可能性，其中药物与靶向基团之间的连接可能在调节这些前药的体内行为中起重要作用。
