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Experimental Biology and Medicine 230:118-127 (2005)
© 2005 Society for Experimental Biology and Medicine

MINIREVIEW

Modulation of p-Glycoprotein Transport Function at the Blood-Brain Barrier

Björn Bauer*, Anika M. S. Hartz*,{dagger}, Gert Fricker{dagger} and David S. Miller*,1

* Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; and {dagger} Institute for Pharmacy and Molecular Biotechnology, University of Heidelberg, D-69120 Heidelberg, Germany

To whom requests for reprints should be addressed at 1 Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709. E-mail: miller{at}niehs.nih.gov

The central nervous system (CNS) effects of many therapeutic drugs are blunted because of restricted entry into the brain. The basis for this poor permeability is the brain capillary endothelium, which comprises the blood-brain barrier. This tissue exhibits very low paracellular (tight-junctional) permeability and expresses potent, multispecific, drug export pumps. Together, these combine to limit use of pharmacotherapy to treat CNS disorders such as brain cancer and bacterial or viral infections. Of all the xenobiotic efflux pumps highly expressed in brain capillary endothelial cells, p-glycoprotein handles the largest fraction of commonly prescribed drugs and thus is an obvious target for manipulation. Here we review recent studies focused on understanding the mechanisms by which p-glycoprotein activity in the blood-brain barrier can be modulated. These include (i) direct inhibition by specific competitors, (ii) functional modulation, and (iii) transcriptional modulation. Each has the potential to specifically reduce p-glycoprotein function and thus selectively increase brain permeability of p-glycoprotein substrates.

Key Words: ATP-binding cassette • central nervous system pharmacotherapy • endothelin • nuclear receptors • regulation




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