Grant: $260,088 - National Institutes of Health - Aug. 10, 2009
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Award Description: Many drugs distribute poorly to brain and this is a central problem in drug development for the treatment of central nervous system (CNS) disorders, including brain cancer, stroke, ischemia, inflammation, infection, and neurodegenerative disease. This issue has been aptly termed ?the problem behind the problem of CNS drug development.? Multiple issues contribute to this effect including low blood-brain barrier (BBB) permeation, active efflux transport, and tight plasma protein binding. The focus of the parent grant R01 NS52484 is on the development and validation of a mechanism-based kinetic model that accurately describes drug uptake and distribution in brain incorporating plasma protein binding. Under disease conditions, such as brain cancer or stroke, the integrity of the BBB is frequently compromised, the activity of efflux transporters is up or down regulated, and the passage of blood constituents, including plasma proteins, is significantly enhanced. Plasma protein passage into brain can markedly impact drug distribution and action within the CNS. In this ARRA Grant Supplement, we put forward a series of experiments designed to test drug delivery and distribution to brain under disease conditions. Specifically, we propose new experiments using two models of brain cancer: human U87 glioma and LX-1 small cell lung carcinona brain metastasis, in immune compromised rats. These tumor models differ significantly in brain tumor vascularity, BBB disruption, expression of vascular efflux transporters, and extent of BBB albumin leakage. Further, lack of drug efficacy due to poor brain drug distribution is a major problem in brain tumor treatment and most anticancer drugs circulate in blood bound highly to plasma protteins. We will investigate the ability of the kinetic model to accurately predict drug uptake and distribution to brain and brain tumor for five anticancer agents ? paclitaxel, vincristine or vinorelbine, irinotecan, etoposide, and temozolomide. Temozolomide binds to plasma proteins only to a limited extent and will serve as a control agent. The other selected drugs have been utilized for central nervous system cancers or brain metastases of lung cancer. The drugs will be compared in uptake between tumor and normal brain tissue in the presence and absence of plasma proteins. A sixth agent, aminoisobutyric acid (AIB), will also be studied as a classic BBB permeability marker. Positive outcomes of this work will be improved understanding of the factors and processes that control drug exposure to the CNS and enhanced ability to select or develop new agents with good brain availability to treat CNS diseases.
Project Description: As defined in the Award Description field
Jobs Summary: Jobs created/retained will be reported in the next period. (Total jobs reported: 0)
Project Status: Less Than 50% Completed
This award's data was last updated on Aug. 10, 2009. Help expand these official descriptions using the wiki below.