Effective systemic treatments for diseases of the central nervous system require therapeutic agents that are able to cross the blood-brain barrier (BBB). Significant efforts are devoted to design drug molecules with the correct permeability characteristics in order to achieve this goal, yet many promising agents are still not able to cross the barrier into the brain in sufficient amounts to achieve therapeutic effectiveness. The olfactory mucosa is one of the few areas of the central nervous system which lack a traditional """"""""blood-brain barrier"""""""", and drug transport directly from the nasal cavity into the brain tissue or cerebrospinal fluid has been observed for a number of compounds. Uptake and efflux membrane transporters play a significant role in determining which drugs can access the CNS from the olfactory mucosa. It is the goal of this research to identify key drug transporters in the nasal mucosa, and to use this information to identify efficient pathways for direct, safe delivery of drugs to the CNS. Amantadine, baclofen and valproic acid will be used to determine the activities of the organic cation-2 transporter, large neutral amino acid carrier, and multi-drug resistance-associated transporters, respectively. Current evidence suggests that each of these protein transporters is present in the nasal mucosa, yet their role in the direct nose-to-brain transport of the substrate drug molecules is unknown. In vitro methods using excised nasal mucosal tissues will be used to determine the affinities and capacities of the transporters for these substrates. Modulation of their behaviors will also be addressed using known transporter inhibitors. In vivo studies will be carried out to determine the extent to which modulation of the transporters might serve as an effective strategy for the optimization of nose-to-brain transport of substrate drug compounds. The public health relevance of this research is that utilization of specific transporters present in the olfactory mucosa for direct CNS targeting may well provide a wealth of new opportunities for the targeted treatment of CNS disorders. New drugs could be designed and synthesized for specific transporter interactions, rather than merely for high passive permeability across the BBB. The resulting significant increase in the number of potentially effective drug molecules, coupled with this simple, accessible site of delivery could provide new, efficacious therapies to treat a multitude of CNS - based disorders. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
1R01DC008374-01A1
Application #
7260706
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (91))
Program Officer
Davis, Barry
Project Start
2007-06-11
Project End
2012-05-31
Budget Start
2007-06-11
Budget End
2008-05-31
Support Year
1
Fiscal Year
2007
Total Cost
$295,422
Indirect Cost
Name
University of Iowa
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Al-Ghabeish, Manar; Scheetz, Todd; Assem, Mahfoud et al. (2015) Microarray Determination of the Expression of Drug Transporters in Humans and Animal Species Used for the Investigation of Nasal Absorption. Mol Pharm 12:2742-54
Dhamankar, Varsha; Assem, Mahfoud; Donovan, Maureen D (2015) Gene expression and immunochemical localization of major cytochrome P450 drug-metabolizing enzymes in bovine nasal olfactory and respiratory mucosa. Inhal Toxicol 27:767-77
Zhang, Hefei; Schmidt, Mark; Murry, Daryl J et al. (2011) Permeation and systemic absorption of R- and S-baclofen across the nasal mucosa. J Pharm Sci 100:2717-23