The association of C3435T single-nucleotide polymorphism, Pgp-glycoprotein gene expression levels and carbamazepine maintenance dose in patients with epilepsy

Zoran Sterjev¹, Gordana Kiteva Trencevska², Emilija Cvetkovska², Igor Petrov², Igor Kuzmanovski², Jasmina T Ribarska³, Aleksandra K Nestorovska¹, Nadica Matevska¹, Zorica Naumovska¹, Suzana Jolevska-Trajkovic³, Aleksandar Dimovski¹, Ljubica Suturkova^1
1Institute of Pharmaceutical Chemistry, Faculty of Pharmacy Skopje, Republic of Macedonia; ²Clinic of Neurology, Faculty of Medicine, Skopje, Republic of Macedonia; ³Institute of Pharmaceutical Analysis, Faculty of Pharmacy Skopje, Republic of Macedonia

Abstract: The ABCB1 gene encodes the P-glycoprotein (Pgp) protein, which is thought to transport various antiepileptic drugs. The single nucleotide polymorphism (SNP) (C3435T) in exon 26 of this gene correlates with the altered expression levels of P-glycoprotein, range of drug response and clinical conditions. In order to investigate the influence of this polymorphism on the susceptibility to and efficacy of carbamazepine therapy, we evaluated the allelic frequency and genotype distribution of this variant in 162 epilepsy patients from the Republic of Macedonia. Statistically significant differences were detected neither in the allelic frequency and genotype distribution between carbamazepine-resistant and carbamazepine-responsive epilepsy patients nor between the subgroups of carbamazepine (CBZ)-responsive patients treated with different CBZ doses. However, the T-allele was enriched in CBZ-responsive patients who required higher maintenance CBZ doses, This observation was substantiated by the findings that the median total plasma levels were the lowest in patients with CC (20 µmol/L) followed by CT (23 µmol/L) and TT (29 µmol/L) genotypes. Patients with a CC genotype also had a higher likelihood of response compared to patients with CT or TT genotypes over a wide range (400–1000 mg/day) of initial doses of CBZ. The T allele showed a reduced expression of ~5% compared to the C allele in peripheral blood mononuclear cells in heterozygotes for the variant. This difference might be translated into ~10% difference in homozygotes for the variant, which would explain the trend towards a dose-dependent efficacy of the CBZ treatment in patients with different genotypes. A larger prospective study is warranted to clarify the clinical utility of a genotype-specific individualized CBZ therapy.

Keywords: multidrug resistance protein 1 (MDR1), ABCB1 C3435T polymorphism, epilepsy treatment, carbamazepine