Model of the proposed role of cell specific MDR1 expression in epileptic brain. Under physiological conditions, when the blood-brain barrier is intact, overexpression of MDR1 (and possibly other drug resistance proteins [5,9]) in endothelial cells causes active net extrusion of drugs from the brain into the vascular lumen (left panel, (1)). A fraction of the AED molecules bypassing the MDR1 barrier (see Fig. 1A) will diffuse into the lipophilic membranes of parenchymal neurons and glia. MDR1 expression in these cells will lead to diminished intracellular sequestration of drugs and may increase their interstitial levels . However, since the total amount of AED in the epileptic tissue is reduced in the first instance by active BBB extrusion, free AED in the extracellular space may still remain below therapeutic concentrations (left panel, (2) and (4)). In addition, MDR1 overexpression in parenchymal astrocytes and neurons affords protection against toxic concentrations of xenobiotics (left panel (2) and (4)). During the transient opening of the BBB due to epileptic activity, AEDs may be back-fluxed into the blood stream by MDR1 expressed at the glial end-feet of perivascular astrocytes, constituting a "second defense barrier" in the brain (left panel, (3)). Right panels A and B schematically summarize these possible roles of MDR1 in epileptic human brain.