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首页> 外文期刊>Archives of Pharmacal Research >Pharmacokinetic and ulcerogenic studies of naproxen prodrugs designed for specific brain delivery
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Pharmacokinetic and ulcerogenic studies of naproxen prodrugs designed for specific brain delivery

机译：萘普生前体药物的药代动力学和致溃疡性研究

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Naproxen (Nap) is an NSAID used as a neuroprotective agent to treat several neurodegenerative diseases. The observed limited brain bioavailability of the drug prompted the design of several chemical delivery systems. We report the synthesis and preliminary in vitro and in vivo investigations of Nap prodrugs with dihydropyridine (I) and ascorbic acid (II) through an ester spacer to target specific brain delivery of Nap. The purpose of this study was to determine the brain bioavailability of Nap after oral administration of the prodrugs in rats. The results showed moderate oral bioavailability of prodrugs (AUC = 53–94 h · μg/mL) in rats compared with parent Nap (AUC = 155 h · μg/mL) at equimolar doses. Contrarily, there was a twofold increase in Nap levels in the brain with the prodrugs compared to parent Nap. The enhanced brain bioavailability may be attributed to the specific carrier system in addition to the reduced percentage of plasma protein binding of Nap. Plasma protein binding of the tested prodrugs was investigated in vitro using equilibrium dialysis. The percentage of plasma free fraction of prodrugs (9–15%) was significantly greater than that of Nap (about 5%) when tested at 20 μM, illustrating more available prodrug to cross the blood brain barrier. A significant decrease in gastric ulcerogenicity of the prodrugs compared with parent Nap was also noted. In conclusion, oral dihydropyridine and ascorbate prodrugs for brain site-specific delivery of Nap may be promising candidates for safe, chronic use of NSAIDs for the treatment of neurodegenerative diseases.
机译：萘普生（Nap）是一种NSAID，用作治疗几种神经退行性疾病的神经保护剂。观察到的有限的大脑生物利用度促使人们设计了几种化学传递系统。我们报告合成和初步的体外和体内Nap前药与二氢吡啶（I）和抗坏血酸（II）通过酯间隔基靶向Nap的特定脑传递的研究。这项研究的目的是确定大鼠口服前药后Nap的脑生物利用度。结果显示，在等摩尔剂量下，与母体Nap（AUC = 155 h·μg/ mL）相比，大鼠中前药的口服生物利用度中等（AUC = 53–94 h·μg/ mL）。相反，与母体Nap相比，前药在大脑中的Nap水平增加了两倍。除了降低的Nap血浆蛋白结合百分比外，增强的大脑生物利用度还可以归因于特定的载体系统。使用平衡透析在体外研究了所测试前药的血浆蛋白结合。在20μM下进行测试时，前药的血浆游离分数百分比（9-15％）显着大于Nap的百分比（约5％），这说明有更多的前药可以穿越血脑屏障。还注意到与亲本Nap相比，前药的胃溃疡原性显着降低。总之，口服二氢吡啶和抗坏血酸前药用于脑部位Nap的特定传递可能是安全，长期使用NSAID治疗神经退行性疾病的有希望的候选药物。

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