title: Increased P-glycoprotein function and level after long-term exposure of four antiepileptic drugs to rat brain microvascular endothelial cells in vitro.
abstract: To investigate whether long-term exposure to four typical antiepileptic drugs (AEDs): phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ) and valproic acid (VPA) can increase P-glycoprotein (P-gp) level and function in primary cultured rat brain microvascular endothelial cells (rBMECs) in vitro, the rBMECs were incubated in culture medium containing indicated drugs (PB, PHT, CBZ, VPA and rifampin) for 60 days in a gradient concentration manner. Age-matched cells were incubated in normal culture medium. After a 60-day exposure to the indicated drugs, P-gp function and level in cells were measured using rhodamine 123 (Rho123) accumulations and Western blot analysis, respectively. Lower Rho123 accumulation in drug-treated cells was found than that in age-matched cells. Cyclosporin A (CsA) and verapamil (Ver) increased Rho123 accumulation both in drug-treated cells and age-matched cells. The magnitude of increased Rho123 accumulation in drug-treated cells was larger than that in age-matched cells. Higher P-gp levels were found to be consistent with decrease of Rho123 accumulation in drug-treated cells. The results verified the hypothesis that long-term exposure to the four antiepileptic drugs can induce P-gp function and level in rBMECs.
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Yang
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Liu
authors.forename: Xiang
authors.initials: X
authors.lastname: Liu
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Zhang
authors.forename: Yu-Chun
authors.initials: YC
authors.lastname: Liu
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Liu
authors.forename: Guang-Ji
authors.initials: GJ
authors.lastname: Wang
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D002220:Carbamazepine / Q000494:pharmacology; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000187:drug effects* / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007202:Indicators and Reagents; D008833:Microcirculation / Q000187:drug effects* / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D010672:Phenytoin / Q000494:pharmacology; D051381:Rats; D020112:Rhodamine 123; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013995:Time; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014635:Valproic Acid / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D007166:Immunosuppressive Agents; D007202:Indicators and Reagents; D026941:Sodium Channel Blockers; D020112:Rhodamine 123; D002220:Carbamazepine; D014635:Valproic Acid; D010672:Phenytoin; D016572:Cyclosporine; D014700:Verapamil; D010634:Phenobarbital