Region-specific overexpression of P-glycoprotein at the blood-brain barrier affects brain uptake of phenytoin in epileptic rats

Recent studies have suggested that overexpression of the multidrug transporter P- glycoprotein ( P- gp) in the hippocampal region leads to decreased levels of antiepileptic drugs and contributes to pharmacoresistance that occurs in a subset of epileptic patients. Whether P- gp expression and function is affected in other brain regions and in organs that are involved in drug metabolism is less studied. Therefore, we investigated P- gp expression in different brain regions and liver of chronic epileptic rats, several months after electrically induced status epilepticus ( SE), using Western blot analysis. P- gp function was determined by measuring phenytoin ( PHT) levels in these brain regions using high- performance liquid chromatography, in the absence and presence of a P- gp- specific inhibitor, tariquidar (TQD). In addition, the pharmacokinetic profile of PHT was determined. PHT concentration was reduced by 20 to 30% in brain regions that had P- gp overexpression ( temporal hippocampus and parahippocampal cortex) and not in brain regions in which P- gp expression was not changed after SE. Inhibition of P- gp by TQD significantly increased the PHT concentration, specifically in regions that showed P- gp overexpression. Despite increased P- gp expression in the liver of epileptic rats, pharmacokinetic analysis showed no significant change of PHT clearance in control versus epileptic rats. These findings show that overexpression of P- gp at the blood- brain barrier of specific limbic brain regions causes a decrease of local PHT levels in the rat brain.