title: Multidrug resistance-associated protein 1 decreases the concentrations of antiepileptic drugs in cortical extracellular fluid in amygdale kindling rats.
abstract: OBJECTIVE
  To investigate whether multidrug resistance-associated protein 1 (MRP1) was responsible for drug resistence in refractory epilepsy in amygdale kindling rats.
  
  
  METHODS
  Rat amygdale kindling was used as a model of refractory epilepsy. The expression of MRP1 mRNA and protein in the brains was examined using RT-PCR and Western blot. MRP1-positive cells in the cortex and hippocampus were studied with immunohistochemical staining. The rats were intraperitoneally injected with phenytoin (50 mg/kg) or carbamazepine (20 mg/kg), and their concentrations in the cortical extracellular fluid were measured using microdialysis and HPLC. Probenecid, a MRP1 inhibitor (40 mmol/L, 50 μL) was administered through an inflow tube into the cortex 30 min before injection of the antiepileptic drugs.
  
  
  RESULTS
  The expression of MRP1 mRNA and protein was significantly up-regulated in the cortex and hippocampus in amygdale kindling rats compared with the control group. Furthermore, the number of MRP1-positive cells in the cortex and hippocampus was also significantly increased in amygdale kindling rats. Microdialysis studies showed that the concentrations of phenytoin and carbamazepine in the cortical extracellular fluid were significantly decreased in amygdale kindling rats. Pre-administration of probenecid could restore the concentrations back to their control levels.
  
  
  CONCLUSIONS
  Up-regulation of MRP1 is responsible for the resistance of brain cells to antiepileptic drugs in the amygdale kindling rats.
authors.affiliation: Department of Neurology, Jinshan Hospital, Fudan University, Shanghai 201508, China. cyh1973131@163.com
authors.forename: Ying-hui
authors.initials: YH
authors.lastname: Chen
authors.forename: Cui-cui
authors.initials: CC
authors.lastname: Wang
authors.forename: Xia
authors.initials: X
authors.lastname: Xiao
authors.forename: Li
authors.initials: L
authors.lastname: Wei
authors.forename: Guoxiong
authors.initials: G
authors.lastname: Xu
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology*; D002220:Carbamazepine / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007696:Kindling, Neurologic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008297:Male; D017551:Microdialysis / Q000379:methods; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010672:Phenytoin / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000927:Anticonvulsants; D002220:Carbamazepine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010672:Phenytoin; D012333:RNA, Messenger; C421109:multidrug resistance-associated protein 1