Blasberg R, Molnar P, Groothius D, Patlak C, Owens E, Fenstermacher J
J Pharmacol Exp Ther. 1984 Dec;231(3):724-35.
A blood-to-tissue transfer constant, K, and tissue blood flow, F, were measured concurrently in seven rats with a total of 19 separate brain tumors induced by intracerebral inoculation of avian sarcoma virus. Regional and local measurements of K and F were obtained using double-label quantitative autoradiography with alpha-[14C]aminoisobutyric acid and [131I]iodoantipyrine, computerized microdensitometry and image analysis. Apparent tissue extraction fractions and capillary permeability-surface area products were calculated for different tumor regions, brain adjacent to tumor and tumor-free brain. The following observations were made: five histological categories of the tumors were found; significant local and regional variations of both K and F were typical in each group, resulting in marked regional variability of permeability-surface area products but more uniform values of apparent extraction fraction; the values of F, K, permeability-surface area products and apparent extraction fraction correlated poorly with morphological features of the tumors (necrosis, cellularity, cytology, location and size); the extraction fraction of alpha-aminoisobutyric acid was usually highest in tumor centers and then decreased in a gradient from tumor periphery through adjacent brain; and regardless of classification or histological features, capillary permeability and surface area, and not tissue perfusion or blood flow, seem to determine the blood-to-tissue transport processes (delivery of bloodborne materials) in most regions of these experimental brain tumors. An operational pharmacokinetic model of drug concentration in tumor tissue is developed and the results of our analysis indicate that increases in capillary permeability such as measured in these studies would not be sufficient to deliver adequate amounts of water-soluble drugs with short plasma half-lives to tumor tissue.
对7只大鼠同时测量了血-组织转运常数K和组织血流量F，这些大鼠经脑内接种禽肉瘤病毒共诱发了19个独立的脑肿瘤。使用α-[14C]氨基异丁酸和[131I]碘安替比林进行双标记定量放射自显影、计算机显微密度测定和图像分析，获得了K和F的区域及局部测量值。计算了不同肿瘤区域、肿瘤邻近脑区和无肿瘤脑区的表观组织摄取分数和毛细血管通透性-表面积乘积。得到以下观察结果：发现肿瘤有5种组织学类型；每组中K和F均存在显著的局部和区域差异，导致通透性-表面积乘积有明显的区域变异性，但表观摄取分数的值更均匀；F、K、通透性-表面积乘积和表观摄取分数的值与肿瘤的形态学特征（坏死、细胞密度、细胞学、位置和大小）相关性较差；α-氨基异丁酸的摄取分数通常在肿瘤中心最高，然后从肿瘤周边到邻近脑区呈梯度下降；无论分类或组织学特征如何，在这些实验性脑肿瘤的大多数区域，似乎是毛细血管通透性和表面积而非组织灌注或血流量决定了血-组织转运过程（血源物质的输送）。建立了肿瘤组织中药物浓度的操作药代动力学模型，我们的分析结果表明，如本研究中所测量的毛细血管通透性增加，不足以将足够量的血浆半衰期短的水溶性药物输送到肿瘤组织。
