PHARMACOKINETICS OF DIRECT BRAIN INFUSION

直接脑部输注的药代动力学

• 批准号: 3782402
• 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/3782402
• 关键词: brain circulation; brain metabolism; carbon; cats; diffusion; drug administration routes; drug delivery systems; fluid flow; indium; injection /infusion; interstitial; neuropharmacology; pharmacokinetics; radionuclides; radiotracer; sucrose; transferrin

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 > 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.

对于许多化合物(神经营养因子、抗体、生长因子、 基因载体、酶)在大脑中的最小扩散严重限制了 直接给药后药物在脑实质内的分布。 我们系统地研究了对流、分子与散体的输运 流体的流动，以增强大小分子的分布， 铟111-转铁蛋白(In111-Tf；分子量80000)和C14-蔗糖(分子量359)，由 在间质输注期间保持压力梯度以产生 大量流经大脑间质。分配量(Vd) 含有1%的输液浓度随时间线性增加 In111-Tf(Vd-Vi=6.1)和C14-蔗糖的输液量(Vi) (Vd-Vi=14.1)。输注后24小时In111-Tf的分布 增加，变得更均匀，并渗透到灰质 发生了。通过利用对流来补充简单的扩散，大大地 大分子和小分子的增强分布可以在 大脑同时达到比药物暴露大几个数量级 全身性暴露。