title: Potential role for human P-glycoprotein in the transport of lacosamide.
abstract: OBJECTIVE
  Antiepileptic drugs (AEDs) do not effectively treat 30-40% of patients with epilepsy. Export of AEDs by P-glycoprotein (Pgp, ABCB1, or MDR1), which is overexpressed in the blood-brain barrier in drug-resistant patients, may be a mechanism for resistance to AEDs. For most recently approved AEDs, whether they are transported by Pgp is unknown. We investigated whether a new AED, lacosamide (LCM), is a substrate of human Pgp.
  
  
  METHODS
  LLC-PK1 and MDCKII cells transfected with the human MDR1 gene were used to determine the substrate status of LCM in concentration equilibrium transport assays (CETAs). An equal concentration of drug was initially loaded in both the apical and basal chambers, and the concentration in both chambers was measured up to 4 h. The experiments were repeated in the presence of the Pgp inhibitors verapamil and tariquidar. Caco-2 assays were used to determine the intrinsic permeability and efflux ratio of LCM as well as its potential to inhibit digoxin, a Pgp substrate.
  
  
  RESULTS
  Lacosamide was transported by MDR1-transfected cells from basolateral to apical sides. The efflux of LCM could be completely blocked by verapamil or tariquidar. In Caco-2 assays, LCM showed high permeability without a significant efflux ratio; it did not inhibit digoxin, a Pgp substrate.
  
  
  CONCLUSIONS
  Although LCM is a substrate of Pgp in CETA, Caco-2 data demonstrated that passive diffusion should play a major role in the overall disposition of LCM. The critical role of Pgp should be addressed in vivo.
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Chunbo
authors.initials: C
authors.lastname: Zhang
authors.forename: Hugues
authors.initials: H
authors.lastname: Chanteux
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zuo
authors.forename: Patrick
authors.initials: P
authors.lastname: Kwan
authors.forename: Larry
authors.initials: L
authors.lastname: Baum
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000081:Acetamides / Q000493:pharmacokinetics*; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002460:Cell Line; D004077:Digoxin / Q000493:pharmacokinetics; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000078334:Lacosamide; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D013552:Swine; D013997:Time Factors; D014162:Transfection; D014316:Tritium / Q000493:pharmacokinetics; D014700:Verapamil / Q000494:pharmacology
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000081:Acetamides; D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D011804:Quinolines; D012333:RNA, Messenger; D014316:Tritium; D020112:Rhodamine 123; D000078334:Lacosamide; D004077:Digoxin; D014700:Verapamil; C402343:tariquidar
keywords: Lacosamide; P-glycoprotein; Transport