Neurotoxic adverse drug effects are prevalent in the elderly. Evidence suggests that these reactions may stem from age-related changes in the blood brain barrier (BBB). The BBB serves as a protective mechanism restricting the biodistribution of blood-borne compounds into the brain. The BBB loses some of its integrity and protective capabilities with age thereby increasing BBB permeability. Enhanced BBB penetration can result in increased drug brain bioavailability and exaggerated neuropharmacologic effects. As few medications have been evaluated for age-dependent changes in BBB transport, general knowledge about this phenomenon is lacking. It is therefore reasonable to examine the influence of age on those active BBB transport systems responsible for limiting drug trafficking into the brain. P-glycoprotein, an efflux transport protein present in endothelial cells of the cerebral microvasculature, functions as a major protective component of the BBB. P-glycoprotein actively extrudes a wide range of structurally dissimilar lipophilic compounds, including drugs, from the central nervous system. The hypothesis to be tested in this investigation is that age-related decreases in BBB P-glycoprotein activity result in enhanced brain uptake of those drugs which are substrates for P-glycoprotein. The current proposal will utilize intracerebral microdialysis and pharmacologic markers, rhodamine 123 and cyclosporine, in an animal model of BBB transport to investigate age-related changes in BBB P-glycoprotein function. The goals of this project are to determine if aging influences brain exposure to medications and whether these effects are mediated by P-glycoprotein.
