The antiepileptic drug lamotrigine is a substrate of mouse and human breast cancer resistance protein (ABCG2).
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.
['Römermann|Kerstin|K|', 'Helmer|Renate|R|', 'Löscher|Wolfgang|W|']
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 D018528:ATP-Binding Cassette Transporters D000241:Adenosine D000818:Animals D000927:Anticonvulsants D019540:Area Under Curve D002247:Carbon Isotopes D002461:Cell Line, Transformed D054659:Diketopiperazines D004285:Dogs D004305:Dose-Response Relationship, Drug D006576:Heterocyclic Compounds, 4 or More Rings D006801:Humans D007093:Imidazoles D000077213:Lamotrigine D051379:Mice D009363:Neoplasm Proteins D021381:Protein Transport D013379:Substrate Specificity D014162:Transfection D014227:Triazines
Lamotrigine Epilepsy P-glycoprotein Phenytoin Phenobarbital Carbamazepine Levetiracetam Topiramate Valproate Ko143 Pharmacoresistance Mitoxantrone PhIP 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 Transporter hypothesis