Rahimy M H, Simpkins J W, Bodor N
Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville 32610.
Drug Des Deliv. 1990 May;6(1):29-40.
Enhanced delivery and sustained release of estradiol (E2) in the brain could have potential clinical applications in the effective treatment of vasomotor "hot flushes" and prostatic cancer. We have, therefore, evaluated a brain-enhanced E2-chemical delivery system (E2-CDS), which is based upon the interconvertible dihydropyridine in equilibrium with pyridinium salt redox reaction. In this study, we evaluated the tissue distributions of E2-Q+ and E2--the inactive and active metabolites of the E2-CDS. Both E2-Q+ and E2 were detected in all tissues analyzed. In peripheral tissues, E2-Q+ and E2 were rapidly cleared, but in brain, concentrations of both compounds exhibited a slow decline with a t1/2 = 8 days. 14 Days after the E2-CDS administration, brain levels of E2-Q+ exceeded plasma levels by 170-fold, fat levels by 20-fold, and liver levels by 8-fold. Similarly, brain-E2 levels exceeded plasma levels by 38-fold, fat levels by 11-fold, and liver levels by 7-fold. Furthermore, levels of E2-Q+ In anterior pituitary, kidney, heart, and lung were initially 2- to 6-fold higher than brain levels, but 14 days after the E2-CDS administration, brain levels of E2-Q+ exceeded E2-Q+ levels in these peripheral tissues by 1.5- to 3-fold. The increased brain/peripheral tissues ratios of E2-Q+ and E2 in rats treated with the E2-CDS support brain-enhanced delivery and sustained release of E2 from this delivery system.
增强雌二醇（E2）在脑内的递送和缓释在有效治疗血管舒缩性“潮热”和前列腺癌方面可能具有潜在的临床应用价值。因此，我们评估了一种基于二氢吡啶与吡啶鎓盐氧化还原反应处于平衡状态的可相互转化的脑增强型E2化学递送系统（E2-CDS）。在本研究中，我们评估了E2-CDS的无活性和活性代谢物E2-Q⁺和E2在组织中的分布情况。在所有分析的组织中均检测到了E2-Q⁺和E2。在周围组织中，E2-Q⁺和E2被迅速清除，但在脑内，这两种化合物的浓度呈缓慢下降趋势，半衰期为8天。给予E2-CDS 14天后，脑内E2-Q⁺水平超过血浆水平170倍、脂肪水平20倍、肝脏水平8倍。同样，脑内E2水平超过血浆水平38倍、脂肪水平11倍、肝脏水平7倍。此外，垂体前叶、肾脏、心脏和肺中的E2-Q⁺水平最初比脑内水平高2至6倍，但给予E2-CDS 14天后，脑内E2-Q⁺水平超过这些周围组织中E2-Q⁺水平1.5至3倍。用E2-CDS处理的大鼠脑/周围组织中E2-Q⁺和E2比例的增加支持了该递送系统对E2的脑增强递送和缓释作用。
