Videbaek C, Ott P, Paulson O B, Knudsen G M
Department of Neurology, University Hospital Rigshospitalet, Copenhagen, Denmark.
J Cereb Blood Flow Metab. 1999 Sep;19(9):948-55. doi: 10.1097/00004647-199909000-00002.
The calculated fraction of receptor ligands available for blood-brain barrier passage in vivo (f(avail)) may differ from in vitro (f(eq)) measurements. This study evaluates the protein-ligand interaction for iomazenil and flumazenil in rats by comparing f(eq) and f(avail). Repeated measurements of blood-brain barrier permeability for two benzodiazepine antagonists were performed in 44 rats by the double-indicator technique. Cerebral blood flow was measured by intracarotid Xe-injection. The apparent permeability-surface product (PSapp) was measured while CBF or bolus composition was changed. Comparison of PSapp obtained in the absence and presence of 5% albumin in the injectate yielded f(avail), whereas f(eq) was measured by equilibrium dialysis. Iomazenil and flumazenil f(avail) was 62% and 82%, respectively, whereas f(eq) was significantly lower, 42% and 61%. The PSapp for iomazenil and flumazenil increased significantly by 89% and 161% after relative CBF increases of 259% and 201%, respectively. The results demonstrate that application of f(eq) in neuroreceptor studies underestimates the plasma input function to the brain. Model simulations render possible that the differences between f(avail) and f(eq) as well as the effect of CBF on PSapp can be caused by capillary heterogeneity.
体内可通过血脑屏障的受体配体计算分数（f(avail)）可能与体外（f(eq)）测量值不同。本研究通过比较f(eq)和f(avail)来评估大鼠体内艾美拉唑和氟马西尼的蛋白-配体相互作用。采用双指示剂技术对44只大鼠的两种苯二氮䓬拮抗剂的血脑屏障通透性进行了重复测量。通过颈动脉注射氙气测量脑血流量。在改变脑血流量或推注成分的同时测量表观通透率-表面积乘积（PSapp）。比较在注射剂中不存在和存在5%白蛋白时获得的PSapp得出f(avail)，而f(eq)通过平衡透析测量。艾美拉唑和氟马西尼的f(avail)分别为62%和82%，而f(eq)显著更低，分别为42%和61%。在脑血流量分别相对增加259%和201%后，艾美拉唑和氟马西尼的PSapp分别显著增加89%和161%。结果表明，在神经受体研究中应用f(eq)会低估大脑的血浆输入功能。模型模拟表明，f(avail)和f(eq)之间的差异以及脑血流量对PSapp的影响可能是由毛细血管异质性引起的。
