Department of Pharmaceutical Sciences and Center for Blood-Brain Barrier Research, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter, Amarillo, TX 79106, USA.
Brain Res. 2013 Sep 19;1531:84-93. doi: 10.1016/j.brainres.2013.07.040. Epub 2013 Jul 31.
Contradictory results have been reported with regard to the effects of various models of hepatic encephalopathy on the blood-brain barrier (BBB) permeability, which may be due partly to the use of brain concentrations of BBB markers without attention to their peripheral pharmacokinetics. The purpose of the current study was to investigate the effects of short-term portacaval anastomosis (PCA), a type B model of hepatic encephalopathy, on the peripheral pharmacokinetics and brain distribution of sodium fluorescein (FL), which is a small molecule marker of BBB passive permeability. A single 25mg/kg dose of FL was administered intravenously to 10-day PCA and sham-operated rats, and serial blood and bile (0-30min) and terminal (30min) brain samples were collected, and the concentrations of FL and its glucuronidated metabolite (FL-Glu) were measured by HPLC. Additionally, the free fractions of FL (fu) in all the plasma samples were determined, and the effects of bile salts on fu were investigated in vitro. Passive permeability of BBB to FL was estimated by brain uptake clearance (Kin) based on both the brain concentrations of FL and plasma concentrations of free (unbound) FL. PCA caused a 26% increase in the fu of FL in plasma, which was due to competition of bile acids with FL for binding to plasma proteins. Additionally, PCA reduced the biliary excretion of FL-Glu by 55%. However, free Kin values (µl/min/g brain) for the sham (0.265±0.034) and PCA (0.228±0.038) rats were not significantly different. It is concluded that whereas 10-day PCA alters the peripheral pharmacokinetics of FL, it does not significantly affect the BBB permeability to the marker.
关于各种肝性脑病模型对血脑屏障（BBB）通透性的影响，已有相互矛盾的结果报告，这可能部分归因于使用脑内 BBB 标志物浓度，而未关注其外周药代动力学。本研究旨在探讨短期门腔静脉分流术（PCA），一种 B 型肝性脑病模型，对小分子 BBB 被动通透性标志物荧光素钠（FL）的外周药代动力学和脑分布的影响。将单次 25mg/kg 的 FL 剂量静脉注射到 10 天 PCA 和假手术大鼠中，并收集连续的血液和胆汁（0-30 分钟）和终末（30 分钟）脑样本，通过 HPLC 测量 FL 和其葡萄糖醛酸化代谢物（FL-Glu）的浓度。此外，还测定了所有血浆样本中 FL 的游离分数（fu），并在体外研究了胆汁盐对 fu 的影响。基于 FL 在脑内的浓度和游离（未结合）FL 在血浆中的浓度，通过脑摄取清除率（Kin）来估计 BBB 对 FL 的被动通透性。PCA 使血浆中 FL 的 fu 增加了 26%，这是由于胆汁酸与 FL 竞争与血浆蛋白结合所致。此外，PCA 使 FL-Glu 的胆汁排泄减少了 55%。然而，假手术（0.265±0.034）和 PCA 大鼠（0.228±0.038）的游离 Kin 值（µl/min/g 脑）没有显著差异。结论是，尽管 10 天 PCA 改变了 FL 的外周药代动力学，但它对标记物的 BBB 通透性没有显著影响。
