title: P-glycoprotein alters blood-brain barrier penetration of antiepileptic drugs in rats with medically intractable epilepsy.
abstract: P-glycoprotein is one of the earliest known multidrug transporters and plays an important role in resistance to chemotherapeutic drugs. In this study, we detected levels of P-glycoprotein and its mRNA expression in a rat brain model of medically intractable epilepsy established by amygdala kindling and drug selection. We investigated whether inhibition of P-glycoprotein affects the concentration of antiepileptic drugs in cortical extracellular fluid. We found that levels of P-glycoprotein and its mRNA expression were upregulated in epileptic cerebral tissue compared with cerebral tissue from normal rats. The concentrations of two antiepileptic drugs, carbamazepine and phenytoin, were very low in the cortical extracellular fluid of rats with medically intractable epilepsy, and were restored after blockade of P-glycoprotein by verapamil. These results show that increased P-glycoprotein levels alter the ability of carbamazepine and phenytoin to penetrate the blood-brain barrier and reduce the concentrations of these agents in extracellular cortical fluid. High P-glycoprotein levels may be involved in resistance to antiepileptic drugs in medically intractable epilepsy.
authors.affiliation: Department of Neurology, The People's Hospital of Shanxi Province, Taiyuan, People's Republic of China.
authors.forename: Aimei
authors.initials: A
authors.lastname: Ma
authors.affiliation: Department of Neurology, Jinshan Hospital, Fudan University, People's Republic of China ; Department of Neurology, Shanghai Medical College, Shanghai, People's Republic of China.
authors.forename: Cuicui
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Neurology, Jinshan Hospital, Fudan University, People's Republic of China ; Department of Neurology, Shanghai Medical College, Shanghai, People's Republic of China.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Chen
authors.affiliation: School of Pharmacy, Shanghai JiaoTong University, Shanghai, People's Republic of China.
authors.forename: Weien
authors.initials: W
authors.lastname: Yuan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002220:Carbamazepine / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004351:Drug Resistance; D004827:Epilepsy / Q000188:drug therapy*; D008297:Male; D010672:Phenytoin / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D015854:Up-Regulation; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D012333:RNA, Messenger; D002220:Carbamazepine; D010672:Phenytoin; D014700:Verapamil
keywords: P-glycoprotein; amygdala kindling; antiepileptic drugs; medically intractable epilepsy; verapamil