The drug-transporter gene ABCB1 polymorphism (C to T) at position 3435 was typed in 315 patients with epilepsy, classified as drug-resistant in 200 and drug-responsive in 115, and 200 controls without epilepsy, in a study at the Institute of Neurology, London, UK. Drug resistance was defined as at least 4 seizures in 1 year with more than 3 appropriate antiepileptic drugs at maximal tolerated doses. Drug responsiveness was complete freedom from seizures for at least a year. Compared with the drug-responsive patients, those with drug-resistant epilepsy were more likely to have the CC genotype at ABCB1 3435 than the TT genotype (p=0.006). The frequency of the CT genotype did not differ between the two groups. The C polymorphism was overrepresented among drug-resistant as compared with drug-responsive patients (p=0.008). [1]
COMMENT. A genetic basis for refractory epilepsy and resistance to antiepileptic drugs (AED) is identified. Most AED are planar lipophilic agents and substrates for the ABCB1 drug-transporter gene. Multidrug-resistance proteins such as ABCB1 are important in the development of refractory epilepsy, and over-expression of these proteins has been demonstrated in the temporal-lobe tissue from patients with epilepsy. By restricting the entry of lipophilic molecules into the brain, the ABCB1 protein may lessen the effective concentration of AED [2]. Both Siddiqui and Pedley and their colleagues caution that the polymorphism in the ABCB1 gene may not be the specific cause of drug resistance, and other associations may be uncovered in different populations. Pharmacogenomics opens a new approach to the development of therapeutic agents in epilepsy.
A loss of Na+ channel drug sensitivity is proposed as a novel mechanism underlying drug, specifically carbamazepine (CBZ), refractory epilepsy [3]. Researchers at the University of Bonn Medical Center, and Charite, Berlin, Germany, studied cellular mechanisms underlying drug resistance in resected hippocampal tissue from patients with temporal lobe epilepsy. The mechanism of action of CBZ, use-dependent block of voltage-dependent Na+ channels, is completely lost in CBZ-resistant patients.