title: In vitro transport profile of carbamazepine, oxcarbazepine, eslicarbazepine acetate, and their active metabolites by human P-glycoprotein.
abstract: OBJECTIVE
  Antiepileptic drugs (AEDs) are widely used not only in the treatment of epilepsy but also as treatments for psychiatric disorders. Pharmacoresistance of AEDs in the treatment of epilepsy and psychiatric disorders is a serious problem. Transport of antiepileptic drugs by P-glycoprotein (Pgp, ABCB1, or MDR1), which is overexpressed in the blood-brain barrier, may be a mechanism for resistance of AEDs. For most AEDs, conflicting evidence precludes consensus on whether they are substrates of Pgp. The objective of this study was to evaluate whether analogs and metabolites of the AED carbamazepine are substrates of human Pgp.
  
  
  METHODS
  Polarized cell lines MDCKII and LLC transfected with the human MDR1 gene were used in the bidirectional transport assay and concentration equilibrium transport assay. The expression of Pgp was detected by real-time polymerase chain reaction (PCR) and immunofluorescent staining. Rhodamine-123 uptake was also determined.
  
  
  RESULTS
  Pgp did not transport carbamazepine, but it did transport its active metabolite carbamazepine-10,11-epoxide. Pgp also pumped eslicarbazepine acetate and oxcarbazepine, as well as their active metabolite (S)-licarbazepine. Transport of the drugs was in the order of ESL>OXC>S-LC>CBZ-E in concentration equilibrium conditions. The transport of these drugs was blocked by Pgp inhibitors tariquidar and verapamil.
  
  
  CONCLUSIONS
  All carbamazepine analogs or metabolites tested are Pgp substrates, except for carbamazepine. These data suggest that resistance to carbamazepine, oxcarbazepine, or eslicarbazepine acetate may be attributed to increased efflux function of Pgp because they or their active metabolites are Pgp substrates.
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Chunbo
authors.initials: C
authors.lastname: Zhang
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: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism*; D001692:Biological Transport; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000378:metabolism*; D002460:Cell Line; D003984:Dibenzazepines / Q000378:metabolism*; D004351:Drug Resistance; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D066298:In Vitro Techniques; D018374:LLC-PK1 Cells / Q000378:metabolism; D000078330:Oxcarbazepine; D016133:Polymerase Chain Reaction; D013552:Swine
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D003984:Dibenzazepines; D002220:Carbamazepine; C416835:eslicarbazepine acetate; D000078330:Oxcarbazepine