Drug Interactions at the Human Blood-Brain Barrier

人体血脑屏障的药物相互作用

• 批准号: 7819832
• 负责人: JASHVANT D Unadkat
• 金额: $ 50万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7819832
• 关键词: AIDS Dementia Complex; Ablation; Address; Alzheimer' s Disease; Amyloid beta-Protein; Antineoplastic Agents; Area; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Central Nervous System Agents; Central Nervous System Diseases; Clinic; Collaborations; Communities; Data; Development; Dexamethasone; Diffuse; Diffusion; Disease; Dose; Drug Delivery Systems; Drug Industry; Drug Interactions; Drug abuse; Drug toxicity; Early Diagnosis; Endothelial Cells; Epilepsy; Excision; FDA approved; Genes; HIV Protease Inhibitors; Human; Hypericum perforatum; Image; In Vitro; Knock-out; Laboratories; Lead; Liquid substance; Literature; Loperamide; Malignant Neoplasms; Marketing; Measures; Methadone; Methods; Multi-Drug Resistance; Mus; Nelfinavir; Neuraxis; Neurodegenerative Disorders; Opioid; Organ; P-Glycoprotein; P-Glycoproteins; Paclitaxel; Pain; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Play; Positron-Emission Tomography; Process; Psyche structure; Quinidine; Rattus; Rifabutin; Rifampin; Rodent; Role; Taxane Compound; The Sun; Therapeutic; Tight Junctions; Time; Toxin; Translational Research; Verapamil; Wild Type Mouse; age related; base; chemical genetics; clinically relevant; clinically significant; design; docetaxel; drug development; drug distribution; drug efficacy; effective therapy; imaging modality; improved; inhibitor/antagonist; innovation; nervous system disorder; neurotoxicity; novel; prevent; public health relevance; taxane; tool development; tumor

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Research and multiple specific Challenge Topics: 15-NS-101* Manipulating the blood-brain-barrier to deliver CNS therapies for Mental/Nervous System Disorders; 06-GM-102* Chemist/biologist collaborations facilitating tool development; 05-AG-103* Imaging and Fluid Biomarkers for Early Diagnosis and Progression of Aging-related Diseases and Conditions including Neurodegenerative Diseases. The blood brain barrier (BBB) is a significant barrier to delivery of drugs to the central nervous system (CNS) and in removal of potential toxins produced within the CNS (e.g. beta-amyloid). In contrast to the endothelial cell barrier in other organs, the BBB has tight junctions that prevent significant paracellular diffusion. Although lipophilic drugs are capable of readily diffusing from the blood to the brain across the BBB, several efflux transporters present at this barrier can significantly reduce the entry of these drugs into the CNS [1]. Prominent amongst these is P-glycoprotein (P-gp), an ABC efflux transporter encoded by the multi-drug resistance 1 (MDR1) gene [2]. Due to its high expression at the BBB and its wide substrate selectivity, P-gp is widely believed to be the most important transporter in modulating the entry of drugs into the CNS, transporting more than 30% of the drugs on the market. The functional importance of P-gp at the BBB was confirmed with the development of the mdr1a(-/-) mice. With ablation of P-gp at the BBB, administration of P-gp substrate drugs to mdr1a(-/-) mice results in a dramatic increase in the brain distribution of these drugs. For example, compared to the wild type mouse, the brain:blood concentration ratio of the anti-HIV protease inhibitor, nelfinavir, is increased 40-fold. Based on the above data, it has been widely predicted that induction or chemical/genetic knock-out of P-gp in rodents is predictive of the magnitude of P-gp activity likely to be observed at the human BBB. If this widely-accepted extrapolation is correct, overcoming the human P-gp BBB will result in significant increase in CNS efficacy of drugs that are P-gp substrates (e.g. anti-HIV protease inhibitors). Conversely, induction of P-gp activity at the human BBB could significantly increase the efflux of potential toxins from the CNS (e.g. beta-amyloid in Alzheimer's disease) or reduce the efficacy of drugs targeted to the CNS for the treatment of pain (e.g. opioids) and other CNS disorders. However, a key question remains unanswered. Is P-gp activity at the human BBB as important as in rodents in preventing delivery of drugs to the brain or in removal of soluble beta-amyloid from the brain? Until recently, this important and clinically relevant question could not be answered as methods to measure P-gp activity or P-gp inhibition/induction at the human BBB were not available. This changed with the development by our laboratory of a novel, innovative and non-invasive, Positron Emission Tomography (PET) imaging method to quantitatively measure P-gp activity and its inhibition/induction at the human BBB. Therefore, our specific aims are designed to address the following key questions: (i) Is P-gp at the human BBB as important as that in rodents in excluding drugs from the CNS (Aims 1 and 2)? (ii) Can P-gp activity at the human BBB be inhibited with currently approved FDA drugs? If so, is the maximum possible inhibition sufficient to significantly increase the delivery of drugs to treat lethal CNS disorders such as brain tumors or to produce profound, but inadvertent, drug interactions (Aim 1)? A negative answer will also be significant in that it will guide clinicians as well as the pharmaceutical industry. Currently, due to concerns of profound P-gp based drug interactions, the pharmaceutical industry avoids (perhaps unnecessarily) development of CNS drugs that are P-gp substrates. Thus, defining the boundaries within which clinically significant P-gp based drug interactions are likely to occur would be enormously helpful in the drug development process and in the clinic. (iii) Can P-gp activity at the human BBB be induced? If so, what is the maximum induction produced by a FDA-approved drug, rifampin, a potent inducer of P-gp (Aim 2)? If P-gp activity at the human BBB is inducible, such a finding would also have considerable clinical significance. First, induction of P-gp at the human BBB, resulting in enhanced clearance of beta-amyloid from the brain, could be a potential novel and innovative therapeutic strategy in the treatment of Alzheimer's disease. Second, such an approach could be used to "tighten" the BBB in the case of drug abuse (e.g. methadone, a P-gp substrate). Third, it would indicate that drugs that are potent P-gp inducers (e.g. St. John's Wort, dexamethasone, rifabutin) must be avoided when co-administered with P-gp substrate drugs targeted to the brain. On completion, the results of our study will have wide ranging implications on multitude of communities including people with Alzheimer's disease, brain tumors, HIV-associated dementia and the entire CNS drug development process in the pharmaceutical industry. PUBLIC HEALTH RELEVANCE: The aims of this proposal will determine if inhibitory or inductive P-glycoprotein based drug interactions can occur at the human blood-brain barrier. In addition, our studies will measure the magnitude of such interactions. The results of our study should lead to better management of drug therapy and improvement of the drug development process.

描述(由申请人提供)：本申请涉及广泛的挑战领域(15)转化研究和多个具体挑战主题：15-NS-101*操纵血脑屏障，为精神/神经系统疾病提供中枢神经系统疗法；06-GM-102*化学家/生物学家合作，促进工具开发；05-AG-103*用于衰老相关疾病和包括神经退行性疾病在内的疾病的早期诊断和进展的成像和流体生物标记物。血脑屏障(BBB)是向中枢神经系统(CNS)输送药物和清除中枢神经系统产生的潜在毒素(如β-淀粉样蛋白)的重要屏障。与其他器官的内皮细胞屏障不同，血脑屏障有紧密的连接，防止了显著的细胞旁扩散。尽管亲脂性药物能够很容易地通过血脑屏障从血液扩散到大脑，但存在于这一屏障的几个外流转运体可以显著减少这些药物进入中枢神经系统[1]。其中最突出的是P-糖蛋白(P-gp)，这是一种由多药耐药1(Mdr1)基因编码的ABC外排转运蛋白[2]。由于其在血脑屏障的高表达和广泛的底物选择性，P-gp被广泛认为是调节药物进入中枢神经系统的最重要的转运体，市场上30%以上的药物被转运。随着mdr1a(-/-)小鼠的发育，P-gp在血脑屏障的功能重要性得到了证实。随着P-gp在血脑屏障的消融，给mdr1a(-/-)小鼠注射P-gp底物药物会导致这些药物在脑内的分布显著增加。例如，与野生型小鼠相比，抗HIV蛋白水解酶抑制剂奈非那韦的脑：血浓度比增加了40倍。基于上述数据，人们普遍预测，P-gp在啮齿动物体内的诱导或化学/遗传敲除可以预测可能在人类血脑屏障观察到的P-gp活性的大小。如果这一被广泛接受的外推是正确的，克服人类P-gp血脑屏障将导致作为P-gp底物的药物(例如，抗HIV蛋白酶抑制剂)的中枢神经系统疗效显著增加。相反，在人的血脑屏障中诱导P-gp活性可能会显著增加潜在毒素从中枢神经系统(例如阿尔茨海默病中的β-淀粉样蛋白)的外流，或降低针对中枢神经系统的药物治疗疼痛(例如阿片类药物)和其他中枢神经系统疾病的疗效。然而，一个关键问题仍然没有得到回答。人类血脑屏障上的P-gp活性在阻止药物输送到大脑或从大脑中清除可溶性β-淀粉样蛋白方面是否与啮齿动物一样重要？直到最近，这个重要的和临床相关的问题还无法得到回答，因为还没有测量P-gp活性或人血脑屏障中P-gp抑制/诱导的方法。随着我们实验室开发出一种新的、创新的、非侵入性的正电子发射断层扫描(PET)成像方法来定量测量P-gp活性及其对人血脑屏障的抑制/诱导，这种情况发生了改变。因此，我们的具体目标旨在解决以下关键问题：(I)在排除中枢神经系统药物方面，人类血脑屏障上的P-gp是否与啮齿动物的P-gp一样重要(目标1和2)？(Ii)目前批准的FDA药物能否抑制人血脑屏障中P-gp的活性？如果是这样的话，最大可能的抑制是否足以显著增加药物的输送，以治疗脑瘤等致命的中枢神经系统疾病，或产生深刻但无意的药物相互作用(目标1)？否定的答案也将具有重要意义，因为它将指导临床医生和制药业。目前，由于对基于P-gp的药物相互作用的担忧，制药业避免(也许是不必要的)开发作为P-gp底物的中枢神经系统药物。因此，确定临床上有意义的基于P-gp的药物相互作用可能发生的界限将在药物开发过程中和临床上有极大的帮助。(Iii)人血脑屏障上的P-gp活性能被诱导吗？如果是，FDA批准的药物利福平产生的最大诱导作用是什么？利福平是P-gp的有效诱导剂(AIM 2)？如果人类血脑屏障上的P-gp活性是可诱导的，这样的发现也将具有相当大的临床意义。首先，在人类血脑屏障诱导P-gp，从而增强脑中β-淀粉样蛋白的清除，可能是治疗阿尔茨海默病的一种潜在的新颖和创新的治疗策略。其次，在滥用药物的情况下，这种方法可以用来“收紧”血脑屏障(例如，P-gp底物美沙酮)。第三，这将表明，当与针对大脑的P-gp底物药物联合给药时，必须避免使用有效的P-gp诱导剂药物(如圣约翰草、地塞米松、利福布汀)。完成后，我们的研究结果将对众多社区产生广泛的影响，包括阿尔茨海默病患者、脑瘤患者、艾滋病毒相关痴呆症患者以及制药业的整个中枢神经系统药物开发过程。 公共卫生相关性：这项提案的目的将决定基于P-糖蛋白的药物相互作用是否可以发生在人的血脑屏障上。此外，我们的研究将测量这种相互作用的大小。我们的研究结果应该会导致更好的药物治疗管理和药物开发过程的改进。