Drug Interactions at the Human Blood-Brain Barrier

人体血脑屏障的药物相互作用

• 批准号: 7938593
• 负责人: JASHVANT D Unadkat
• 金额: $ 49.98万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938593
• 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）：该申请涉及广泛的挑战领域（15）转化研究和多个特定的挑战主题：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治疗；06-GM-102*化学家/生物学家合作促进工具开发；*成像和液体生物标志物用于早期诊断和衰老相关疾病的进展，包括神经退行性疾病。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（CNS）内产生的潜在毒素（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，血脑屏障具有紧密的连接，可防止显著的细胞旁扩散。虽然亲脂性药物能够很容易地从血液通过血脑屏障扩散到大脑，但存在于血脑屏障的几种外排转运蛋白可以显著减少这些药物进入中枢神经系统血脑屏障。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[2]编码的ABC外排转运蛋白。由于其在血脑屏障处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蛋白，转运市场上30%以上的药物。通过mdr1a（-/-）小鼠的发育证实了P-gp在血脑屏障中的功能重要性。随着血脑屏障处P-gp的消融，将P-gp底物药物给予mdr1a（-/-）小鼠可导致这些药物在脑内分布的急剧增加。例如，与野生型小鼠相比，抗hiv蛋白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，啮齿动物中P-gp的诱导或化学/遗传敲除可以预测在人类血脑屏障中可能观察到的P-gp活性的大小。如果这一被广泛接受的推断是正确的，那么克服人类P-gp血脑屏障将导致P-gp底物药物（例如抗hiv蛋白酶抑制剂）的中枢神经系统功效显著增加。相反，在人血脑屏障处诱导P-gp活性可以显著增加中枢神经系统潜在毒素的外排（如阿尔茨海默病中的β -淀粉样蛋白）或降低靶向中枢神经系统治疗疼痛的药物（如阿片类药物）和其他中枢神经系统疾病的疗效。然而，一个关键问题仍未得到解答。人类血脑屏障上的P-gp活性是否与啮齿类动物一样重要，能阻止药物进入大脑或从大脑中去除可溶性β -淀粉样蛋白？直到最近，这个重要的和临床相关的问题还不能回答，因为没有测量P-gp活性或P-gp在人血脑屏障中的抑制/诱导的方法。随着我们实验室开发出一种新颖、创新和无创的正电子发射断层扫描（PET）成像方法，定量测量P-gp活性及其在人血脑屏障中的抑制/诱导，这种情况发生了变化。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是否与啮齿动物中的P-gp一样重要（目标1和2）？（ii）目前FDA批准的药物能否抑制人血脑屏障的P-gp活性？如果是这样，最大可能的抑制是否足以显著增加药物的递送，以治疗致命的中枢神经系统疾病，如脑肿瘤，或产生深刻但无意的药物相互作用（Aim 1）？一个否定的答案也将是重要的，因为它将指导临床医生以及制药行业。目前，由于对基于P-gp的药物相互作用的担忧，制药行业避免（可能不必要地）开发P-gp底物的中枢神经系统药物。因此，确定基于P-gp的药物可能发生临床显著相互作用的边界，将对药物开发过程和临床非常有帮助。（iii）能否诱导人血脑屏障P-gp活性？如果是这样，fda批准的药物利福平（一种强效P-gp诱导剂）产生的最大诱导量是多少？如果人类血脑屏障的P-gp活性是可诱导的，这一发现也将具有相当大的临床意义。首先，在人血脑屏障诱导P-gp，从而增强大脑对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，在药物滥用的情况下，这种方法可以用来“收紧”血脑屏障（例如美沙酮，P-gp底物）。第三，这将表明，强效P-gp诱导剂药物（如圣约翰草、地塞米松、利法布汀）在与靶向脑的P-gp底物药物联合使用时必须避免使用。完成后，我们的研究结果将对包括阿尔茨海默病，脑肿瘤，艾滋病毒相关痴呆患者在内的众多社区以及制药行业的整个中枢神经系统药物开发过程产生广泛的影响。