神经退行性疾病对药物与脑组织结合的影响：从动物模型到人体样本。
Impact of Neurodegenerative Diseases on Drug Binding to Brain Tissues: From Animal Models to Human Samples.
机构信息
Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Avenida Pio XII 55, 31008, Pamplona, Spain.
Imaging Unit and Cancer Imaging Laboratory, University of Navarra, Avenida Pio XII 55, 31008, Pamplona, Spain.
出版信息
Neurotherapeutics. 2018 Jul;15(3):742-750. doi: 10.1007/s13311-018-0624-5.
Drug efficacy in the central nervous system (CNS) requires an additional step after crossing the blood-brain barrier. Therapeutic agents must reach their targets in the brain to modulate them; thus, the free drug concentration hypothesis is a key parameter for in vivo pharmacology. Here, we report the impact of neurodegeneration (Alzheimer's disease (AD) and Parkinson's disease (PD) compared with healthy controls) on the binding of 10 known drugs to postmortem brain tissues from animal models and humans. Unbound drug fractions, for some drugs, are significantly different between healthy and injured brain tissues (AD or PD). In addition, drugs binding to brain tissues from AD and PD animal models do not always recapitulate their binding to the corresponding human injured brain tissues. These results reveal potentially relevant implications for CNS drug discovery.
中枢神经系统 (CNS) 的药物疗效需要在穿过血脑屏障后再增加一个步骤。治疗药物必须到达大脑中的靶标才能对其进行调节；因此，游离药物浓度假说成为体内药理学的一个关键参数。在这里，我们报告了神经退行性变（与健康对照组相比，阿尔茨海默病 (AD) 和帕金森病 (PD)）对 10 种已知药物与动物模型和人类死后脑组织结合的影响。对于某些药物，未结合的药物分数在健康和受损脑组织（AD 或 PD）之间存在显著差异。此外，与 AD 和 PD 动物模型脑组织结合的药物并不总是能重现其与相应人损伤脑组织的结合。这些结果揭示了对 CNS 药物发现具有潜在相关意义。
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