PHARMACOKINETICS OF DIRECT BRAIN INFUSION

直接脑部输注的药代动力学

• 批准号: 5203956
• 负责人: E H OLDFIELD
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5203956
• 关键词: Primates; brain circulation; brain metabolism; diffusion; drug administration routes; drug delivery systems; fluid flow; injection /infusion; interstitial; laboratory rat; neuropharmacology; nonblood rheology; perfusion; pharmacokinetics; radiotracer

For many compounds (neurotrophic factors, antibodies, growth factors, genetic vectors, enzymes) minimal diffusion in the brain severely limits drug distribution after direct drug administration in to brain parenchyma. We systemically investigated convection, molecular transport with bulk flow of fluid, to enhance the distribution of large and small molecules, indium111-transferrin (In111-Tf; MW 80,000) and C14-sucrose (MW 359), by maintaining a pressure gradient during interstitial infusion to generate bulk flow through the brain interstitium. The volume of distribution (Vd) containing greater than or equal to 1% of infusate concentration increased linearly with the infusion volume (Vi) for In111- Tf (Vd/Vi=6.1) and C14-sucrose (Vd/Vi=14.1). 24 hr after infusion, the distribution of In111-Tf increased, became more homogeneous, and penetration into gray matter occurred. By using convection to supplement simple diffusion, greatly enhanced distribution of large and small molecules can be achieved in the brain while achieving drug exposure orders of magnitude greater than systemic exposure. Convection-enhances distribution was shown to be an effective technique to homogeneously deliver large and small molecules in the gray matter of rats and non- human primates. the infusion of molecular selectively toxic to certain subsets of neurons is now being investigated as a potential new therapeutic strategy for Parkinson's disease and for seizures. Continuous perfusion of most of the cerebral hemisphere of monkeys was achieved for several days with an implanted controllable pump.

对于许多化合物（神经营养因子、抗体、生长因子、 遗传载体、酶）在大脑中的最小扩散严重限制了 直接给药至大脑后的药物分布 薄壁组织。 我们系统地研究了对流、分子输运 具有散流流体，增强大、小分布 分子，铟111-转铁蛋白（In111-Tf；MW 80,000）和C14-蔗糖 (MW 359)，通过在间质输注期间保持压力梯度 产生通过脑间质的大量流量。体积为 含有大于或等于 1% 输注液的分布 (Vd) In111- 浓度随输注量 (Vi) 线性增加 Tf (Vd/Vi=6.1) 和 C14-蔗糖 (Vd/Vi=14.1)。 输注后24小时， In111-Tf 的分布增加，变得更加均匀，并且 发生了对灰质的渗透。 通过对流来补充 简单扩散，大大增强大小分布 分子可以在大脑中实现药物暴露的同时 比系统性暴露高出几个数量级。对流增强 分布被证明是一种有效的均匀技术 在大鼠和非大鼠的灰质中传递大分子和小分子 人类灵长类动物。 分子选择性毒性的输注 神经元子集现在正在作为潜在的新的研究对象进行研究 帕金森病和癫痫发作的治疗策略。 对猴子的大部分大脑半球进行持续灌注 通过植入可控泵几天即可实现。