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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
NIH Challenge Grants and Partnerships Program (RC1)
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Special Emphasis Panel (ZRG1-MDCN-A (58))
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Jacobs, Tom P
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University of Washington
Schools of Pharmacy
United States
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