Abstracts

P-glycoprotein (P-gp) has been implicated in the causation of refractory epilepsy. Elevated expression of this efflux transporter has been reported in the vicinity of intractable epileptic foci and several commonly used antiepileptic drugs (AEDs) have been proposed as substrates for P-gp mediated transport. The expression and efflux efficiency of P-gp can be influenced by a specific single nucleotide polymorphism in the encoding gene ([italic]ABCB1[/italic]). We have investigated the capacity of this polymorphism to predict response to initial AED monotherapy in patients with previously untreated, newly diagnosed epilepsy.
Genomic DNA samples were obtained from a subset of patients undertaking a randomised, open-label study of sodium valproate (VPA; n=39) and lamotrigine (LTG; n=52) monotherapy in newly diagnosed epilepsy, irrespective of seizure type. Genotype of the C3435T polymorphism in the [italic]ABCB1[/italic] gene was determined by PCR amplification of a 197 bp fragment of exon 26 by specific primers, restriction digest with Dpn II endonuclease for 4 hours at 37[deg]C, and UV resolution on a 2.5% agarose gel stained with ethidium bromide. Clinical classification of response to treatment was undertaken in a blinded fashion by an independent physician. Results were expressed as percentage of individual genotype per response group and compared by logistical regression analysis.
A total of 54 patients (28 VPA, 26 LTG) were seizure-free for at least six months on initial monotherapy. The remaining 37 patients (11 VPA, 26 LTG) were considered as incomplete or inadequate responders. In the study population as a whole (n=91), the relative frequencies of individual genotypes were 17.6% CC, 51.6% CT and 30.8% TT. Comparison of seizure-free and non-seizure-free patients (irrespective of treatment) revealed no significant difference in genotype frequencies (e.g. CC vs TT; odds ratio = 1.11, 95% CI = 0.324 to 3.83, p=0.558). There were similarly no significant differences in genotype frequencies when analyses were restricted to VPA or LTG treated patients alone.
This study is the first prospective investigation of [italic]ABCB1[/italic] polymorphisms in a representative cross-section of newly diagnosed epilepsy. The C3435T polymorphism in exon 26 of the [italic]ABCB1[/italic] gene did not adequately predict response to initial monotherapy in this population.