title: The antiepileptic drug lamotrigine is a substrate of mouse and human breast cancer resistance protein (ABCG2).
abstract: Resistance to antiepileptic drugs (AEDs) is the major problem in the treatment of epilepsy. One hypothesis to explain AED resistance suggests that seizure-induced overexpression of efflux transporters at the blood-brain barrier (BBB) restricts AEDs to reach their brain targets. Various studies examined whether AEDs are substrates of P-glycoprotein (Pgp; MDR1; ABCB1), whereas information about the potential role of breast cancer resistance protein (BCRP; ABCG2) is scanty. We used a highly sensitive in vitro assay (concentration equilibrium transport assay; CETA) with MDCKII cells transduced with murine Bcrp1 or human BCRP to evaluate whether AEDs are substrates of this major efflux transporter. Six of 7 AEDs examined, namely phenytoin, phenobarbital, carbamazepine, levetiracetam, topiramate, and valproate, were not transported by Bcrp at therapeutic concentrations, whereas lamotrigine exhibited a marked asymmetric, Bcrp-mediated transport in the CETA, which could be almost completely inhibited with the Bcrp inhibitor Ko143. Significant but less marked transport of lamotrigine was determined in MDCK cells transfected with human BCRP. Lamotrigine is also a substrate of human Pgp, so that this drug is the first AED that has been identified as a dual substrate of the two major human efflux transporters at the BBB. Previous in vivo studies have demonstrated a synergistic or cooperative role of Pgp and Bcrp in the efflux of dual substrates at the BBB, so that transport of lamotrigine by Pgp and BCRP may be an important mechanism of pharmacoresistance in epilepsy patients in whom both transporters are overexpressed.
authors: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany.
authors: Kerstin
authors: K
authors: Römermann
authors: Pharmacological Laboratory of the Society for Epilepsy Research, Epilepsy Center Bethel, Bielefeld, Germany.
authors: Renate
authors: R
authors: Helmer
authors: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany. Electronic address: wolfgang.loescher@tiho-hannover.de.
authors: Wolfgang
authors: W
authors: Löscher
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D002461:Cell Line, Transformed; D054659:Diketopiperazines; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000493:pharmacokinetics; D000077213:Lamotrigine; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D013379:Substrate Specificity / Q000187:drug effects; D014162:Transfection; D014227:Triazines / Q000494:pharmacology*
chemical_list: C541506:3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester; C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000927:Anticonvulsants; D002247:Carbon Isotopes; D054659:Diketopiperazines; D006576:Heterocyclic Compounds, 4 or More Rings; D007093:Imidazoles; D009363:Neoplasm Proteins; D014227:Triazines; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D000241:Adenosine; D000077213:Lamotrigine
keywords: Carbamazepine; Epilepsy; Ko143; Lamotrigine; Levetiracetam; Mitoxantrone; P-glycoprotein; PhIP; Pharmacoresistance; Phenobarbital; Phenytoin; PubChem CID: 10322450; PubChem CID: 148201; PubChem CID: 1530; PubChem CID: 1775; PubChem CID: 2554; PubChem CID: 3121; PubChem CID: 3878); PubChem CID: 4212; PubChem CID: 4763; PubChem CID: 5284; PubChem CID: 5284627; Tariquidar; Topiramate; Transporter hypothesis; Valproate