The influence of C3435T polymorphism of ABCB1 gene on penetration of phenobarbital across the blood-brain barrier in patients with generalized epilepsy

Bašić, Silvio and Hajnšek, Sanja and Božina, Nada and Filipčić, Igor and Sporiš, Davor and Mišlov, Damir and Posavec, Ana (2008) The influence of C3435T polymorphism of ABCB1 gene on penetration of phenobarbital across the blood-brain barrier in patients with generalized epilepsy. Seizure, 17 (6). pp. 524-530. ISSN 1059-1311 (Print)

[img]
Preview
PDF
Download (162kB) | Preview

Abstract

BACKGROUND: Epilepsy is refractory to medical treatment in about one-third of the patients. The exact pathological mechanism of epilepsy pharmacoresistance is still unclear, but a decreased antiepileptic drug (AED) uptake into the brain is suspected to play a role. P-glycoprotein (Pgp), a transmembrane transporter encoded by ABCB1 gene and located at the endothelial cells of the blood-brain barrier (BBB), has been associated with epilepsy pharmacoresistance. ----- OBJECTIVE: To analyze the effect of two ABCB1 gene polymorphisms, C3435T and G2677T/A, on phenobarbital (PB) concentrations in the cerebrospinal fluid (CSF) and serum (S) and to assess the relationship of ABCB1 polymorphisms to phenobarbital penetration across BBB in vivo and seizure frequency. ----- METHODS: CSF PB and S PB concentrations were measured in 60 patients with idiopathic primary generalized epilepsy receiving phenobarbital monotherapy. CSF/S PB concentration ratio was calculated as an index of phenobarbital penetration across BBB. The patients were genotyped for the ABCB1 gene C3435T and G2677T/A polymorphisms. Seizure frequency was recorded during the 6-month phenobarbital monotherapy. ----- RESULTS: Patients with different C3435T polymorphism had significantly different CSF PB concentrations and CSF/S PB concentration ratio. In comparison with CT heterozygotes and TT homozygotes, CC homozygotes had a significantly lower CSF PB concentration (p=0.006) and CSF/PB concentration ratio (p<0.001). G2677T/A polymorphism showed no such effect (p=0.466). CC genotype and low CSF/S PB concentration ratio correlated with increased seizure frequency. ----- CONCLUSIONS: C3435T polymorphism of ABCB1 gene was demonstrated in vivo to significantly influence the CSF/S PB concentration ratio and seizure frequency.

Item Type: Article
MeSH: Polymorphism, Genetic ; ATP-Binding Cassette Transporters - genetics ; Blood-Brain Barrier - drug effects - physiopathology ; Epilepsy, Generalized - drug therapy - genetics - metabolism ; Phenobarbital - blood - cerebrospinal fluid - pharmacology ; Adult ; Female ; Genotype ; Humans ; Male ; Middle Aged ;
Departments: Katedra za neurologiju
Depositing User: Boris Čičovački
Status: Published
Creators:
CreatorsEmail
Bašić, SilvioUNSPECIFIED
Hajnšek, SanjaUNSPECIFIED
Božina, NadaUNSPECIFIED
Filipčić, IgorUNSPECIFIED
Sporiš, DavorUNSPECIFIED
Mišlov, DamirUNSPECIFIED
Posavec, AnaUNSPECIFIED
Date: September 2008
Date Deposited: 01 Dec 2008
Last Modified: 23 Sep 2011 16:10
Subjects: /
Related URLs:
    URI: http://medlib.mef.hr/id/eprint/531

    Actions (login required)

    View Item View Item

    Downloads

    Downloads per month over past year