title: The influence of C3435T polymorphism of ABCB1 gene on penetration of phenobarbital across the blood-brain barrier in patients with generalized epilepsy.
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.
authors.affiliation: Department of Neurology, Zagreb University Hospital Center, Kispatićeva 12, 10 000 Zagreb, Croatia. silvio.basic@zd.t-com.hr
authors.forename: Silvio
authors.initials: S
authors.lastname: Basic
authors.forename: Sanja
authors.initials: S
authors.lastname: Hajnsek
authors.forename: Nada
authors.initials: N
authors.lastname: Bozina
authors.forename: Igor
authors.initials: I
authors.lastname: Filipcic
authors.forename: Davor
authors.initials: D
authors.lastname: Sporis
authors.forename: Damir
authors.initials: D
authors.lastname: Mislov
authors.forename: Ana
authors.initials: A
authors.lastname: Posavec
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000503:physiopathology; D004829:Epilepsy, Generalized / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010634:Phenobarbital / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D011110:Polymorphism, Genetic
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D010634:Phenobarbital