title: Region-specific overexpression of P-glycoprotein at the blood-brain barrier affects brain uptake of phenytoin in epileptic rats.
abstract: 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.
authors: Epilepsy Institute of The Netherlands, Heemstede, The Netherlands.
authors: E A
authors: EA
authors: van Vliet
authors: R
authors: R
authors: van Schaik
authors: P M
authors: PM
authors: Edelbroek
authors: R A
authors: RA
authors: Voskuyl
authors: S
authors: S
authors: Redeker
authors: E
authors: E
authors: Aronica
authors: W J
authors: WJ
authors: Wadman
authors: J A
authors: JA
authors: Gorter
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D010672:Phenytoin / Q000493:pharmacokinetics*; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D011804:Quinolines; D010672:Phenytoin; C402343:tariquidar