title: Lack of interactions between breast cancer resistance protein (bcrp/abcg2) and selected antiepileptic agents.
abstract: OBJECTIVE
  Recent studies have indicated constitutive expression of efflux transporter, breast cancer resistance protein (BCRP, ABCG2), in endothelial cells of the blood-brain barrier (BBB). In epileptogenic brain tumors such as ganglioma, astrocytoma, anaplastic astrocytomas, or glioma multiforme, strong expression of BCRP in the microvasculature of the BBB was observed. Therefore it was hypothesized that this phenomenon could critically influence the bioavailability of drugs in these tumors and potentially contribute to the failure of antiepileptic treatment. The aim of this study was to test whether some commonly used antiepileptic drugs (AEDs) are substrates transported by human BCRP. In particular, we focused on phenobarbital, phenytoin, ethosuximide, primidone, valproate, carbamazepine, clonazepam, and lamotrigine. Furthermore, the inhibitory potency of these AEDs to BCRP was examined.
  
  
  METHODS
  To study substrate affinity of tested AEDs to BCRP, transport experiments were performed in epithelial BCRP-expressing MDCKII-BCRP and MDCKII-parent cell lines cultured on microporous membrane. For detection of inhibitory potency of AEDs to BCRP, accumulation assays were carried out in MEF3.8-BCRP cells with known BCRP substrates, BODIPY FL prazosin and mitoxantrone.
  
  
  RESULTS
  No obvious interactions of tested AEDs with BCRP transporter were observed. Therefore these drugs in relevant therapeutic concentrations are neither substrates nor inhibitors of BCRP.
  
  
  CONCLUSIONS
  Based on our in vitro data we can conclude that resistance to treatment with the tested AEDs probably is not caused by the overexpression of BCRP in the BBB of epileptogenic brain tumors.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague.
authors.forename: Lukas
authors.initials: L
authors.lastname: Cerveny
authors.forename: Petr
authors.initials: P
authors.lastname: Pavek
authors.forename: Jana
authors.initials: J
authors.lastname: Malakova
authors.forename: Frantisek
authors.initials: F
authors.lastname: Staud
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Fendrich
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D004347:Drug Interactions; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004827:Epilepsy / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics; D014162:Transfection
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000927:Anticonvulsants; D009363:Neoplasm Proteins