Al-Ghananeem Abeer M, Traboulsi Ashraf A, Dittert Lewis W, Hussain Anwar A
Division of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky 40536, USA.
AAPS PharmSciTech. 2002;3(1):E5. doi: 10.1208/pt030105.
The utility of the nasal route for the systemic delivery of 17beta-estradiol was studied using watersoluble prodrugs of 17beta-estradiol. This delivery method was examined to determine if it will result in preferential delivery to the brain. Several alkyl prodrugs of 17beta-estradiol were prepared and their physicochemical properties were determined. In vitro hydrolysis rate constants in buffer, rat plasma, and rat brain homogenate were determined by high-performance liquid chromatography. In vivo nasal experiments were carried out on rats. Levels of 17beta-estradiol in plasma and cerebral spinal fluid (CSF) were determined with radioimunoassay using a gamma counter. The study revealed that the aqueous solubilities of the prodrugs were several orders of magnitude greater than 17beta-estradiol with relatively fast in vitro conversion in rat plasma. Absorption was fast following nasal delivery of the prodrugs with high bioavailability. CSF 17beta-estradiol concentration was higher following nasal delivery of the prodrugs compared to an equivalent intravenous dose. It was determined that water-soluble prodrugs of 17beta-estradiol can be administered nasally. These prodrugs are capable of producing high levels of estradiol in the CSF and as a result may have a significant value in the treatment of Alzheimer's disease.
使用17β-雌二醇的水溶性前药研究了鼻腔途径用于17β-雌二醇全身给药的效用。对这种给药方法进行了研究，以确定其是否会导致药物优先输送至脑部。制备了几种17β-雌二醇的烷基前药并测定了它们的理化性质。通过高效液相色谱法测定在缓冲液、大鼠血浆和大鼠脑匀浆中的体外水解速率常数。在大鼠身上进行了体内鼻腔实验。使用γ计数器通过放射免疫分析法测定血浆和脑脊液（CSF）中17β-雌二醇的水平。研究表明，前药的水溶性比17β-雌二醇大几个数量级，并且在大鼠血浆中具有相对较快的体外转化速度。鼻腔给予前药后吸收迅速，生物利用度高。与等效静脉剂量相比，鼻腔给予前药后脑脊液中17β-雌二醇浓度更高。已确定17β-雌二醇的水溶性前药可经鼻腔给药。这些前药能够在脑脊液中产生高水平的雌二醇，因此可能在阿尔茨海默病的治疗中具有重要价值。
