Greig N H, Soncrant T T, Shetty H U, Momma S, Smith Q R, Rapoport S I
Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892.
Cancer Chemother Pharmacol. 1990;26(4):263-8. doi: 10.1007/BF02897227.
Unidirectional blood-brain barrier transfer of the lipophilic anticancer agents vincristine and vinblastine was studied in anesthetized rats, using an isolated, in situ brain perfusion technique. Drug binding to plasma constituents was also measured. Despite the high lipophilicity of these agents (the log octanol/physiological saline partition coefficient equalled 2.14 and 1.68, respectively), the cerebrovascular permeability-surface area product, PA, of vincristine in plasma was only 0.49 x 10(-4) ml s-1 g-1 for parietal cerebral cortex, whereas that of vinblastine was too low for determination. These values are similar to those of water-soluble, poorly diffusible nonelectrolytes. The PAs were significantly higher in the absence of plasma protein, being 1.24 x 10(-4) and 5.36 x 10(-4) ml s-1 g-1, respectively. Even these values, determined by brain perfusion of protein-free buffer, were lower than would be expected from the lipophilicity of the agents. The results suggest that additional factors, such as steric hindrance and molecular charge distribution, related to the chemical and geometric structure and the large size of vincristine and vinblastine (molecular weight, 825 and 814 daltons, respectively) restrict their passage across the blood-brain barrier. As a consequence of their paradoxically low permeability at the blood-brain barrier and restrictive binding to plasma and blood constituents, doses of both agents that cause significant inhibition of extracerebral Walker 256 carcinosarcoma tumor implants in rat have no effect on tumor located in the brain.
采用离体原位脑灌注技术，在麻醉大鼠中研究了亲脂性抗癌药物长春新碱和长春碱的单向血脑屏障转运。还测定了药物与血浆成分的结合情况。尽管这些药物具有高亲脂性（正辛醇/生理盐水分配系数的对数值分别为2.14和1.68），但长春新碱在血浆中的脑血管通透表面积乘积PA，对于顶叶大脑皮层仅为0.49×10⁻⁴ ml s⁻¹ g⁻¹，而长春碱的该值过低无法测定。这些数值与水溶性、扩散性差的非电解质相似。在没有血浆蛋白时，PA值显著更高，分别为1.24×10⁻⁴和5.36×10⁻⁴ ml s⁻¹ g⁻¹。即使是通过无蛋白缓冲液脑灌注测定的这些数值，也低于根据药物亲脂性预期的值。结果表明，与长春新碱和长春碱的化学和几何结构以及大尺寸（分子量分别为825和814道尔顿）相关的其他因素，如空间位阻和分子电荷分布，限制了它们通过血脑屏障。由于它们在血脑屏障处的通透性反常地低以及与血浆和血液成分的结合受限，在大鼠中能显著抑制脑外Walker 256癌肉瘤肿瘤植入的这两种药物剂量，对位于脑内的肿瘤没有作用。
