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In vitro transport profile of carbamazepine, oxcarbazepine, eslicarbazepine acetate, and their active metabolites by human P-glycoprotein.
Epilepsia 2011; 52(10):1894-904E

Abstract

PURPOSE

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.

KEY FINDINGS

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.

SIGNIFICANCE

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+Show Affiliations

School of Pharmacy, The Chinese University of Hong Kong, Shatin, Hong Kong, China.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21692796

Citation

Zhang, Chunbo, et al. "In Vitro Transport Profile of Carbamazepine, Oxcarbazepine, Eslicarbazepine Acetate, and Their Active Metabolites By Human P-glycoprotein." Epilepsia, vol. 52, no. 10, 2011, pp. 1894-904.
Zhang C, Zuo Z, Kwan P, et al. In vitro transport profile of carbamazepine, oxcarbazepine, eslicarbazepine acetate, and their active metabolites by human P-glycoprotein. Epilepsia. 2011;52(10):1894-904.
Zhang, C., Zuo, Z., Kwan, P., & Baum, L. (2011). In vitro transport profile of carbamazepine, oxcarbazepine, eslicarbazepine acetate, and their active metabolites by human P-glycoprotein. Epilepsia, 52(10), pp. 1894-904. doi:10.1111/j.1528-1167.2011.03140.x.
Zhang C, et al. In Vitro Transport Profile of Carbamazepine, Oxcarbazepine, Eslicarbazepine Acetate, and Their Active Metabolites By Human P-glycoprotein. Epilepsia. 2011;52(10):1894-904. PubMed PMID: 21692796.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro transport profile of carbamazepine, oxcarbazepine, eslicarbazepine acetate, and their active metabolites by human P-glycoprotein. AU - Zhang,Chunbo, AU - Zuo,Zhong, AU - Kwan,Patrick, AU - Baum,Larry, Y1 - 2011/06/21/ PY - 2011/6/23/entrez PY - 2011/6/23/pubmed PY - 2011/12/13/medline SP - 1894 EP - 904 JF - Epilepsia JO - Epilepsia VL - 52 IS - 10 N2 - PURPOSE: 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. KEY FINDINGS: 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. SIGNIFICANCE: 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. SN - 1528-1167 UR - https://www.unboundmedicine.com/medline/citation/21692796/In_vitro_transport_profile_of_carbamazepine_oxcarbazepine_eslicarbazepine_acetate_and_their_active_metabolites_by_human_P_glycoprotein_ L2 - https://doi.org/10.1111/j.1528-1167.2011.03140.x DB - PRIME DP - Unbound Medicine ER -