Effect of the P24T polymorphism of the UGT1A4 gene on the effectiveness of therapy with lamotrigine

The association between allelic variants of uridine diphosphate glucuronosyltransferase (UGT1A4) gene and therapeutic dose and plasma concentration of lamotrigine was studied in patients with different forms of epilepsy. Genotyping for the P24T UGT1A4 polymorphism was performed in 50 patients using polymerase-chain reaction. The homozygous major genotype (AA) and heterozygous genotype (AC) were identified. There were no patients with the homozygous minor genotype (CC). Mean effective doses of lamotrigine were 120,9 +/- 8,7 mg/day and 135,7 +/- 24,3 mg/day for the AA and the AC genotypes, respectively, i.e. carriers of the heterozygous genotype needed higher dose of the drug for the maintenance of clinical effect compared to carriers of the AA genotype. The same trend was observed for peak concentrations: 0,83 +/- 0,06 for the AA genotype and 0,93 +/- 0,162 for the AC genotype. However the data analysis revealed no significant between-genotype differences for either lamotrigine doses or peak concentrations. According to 3D modeling data, the process of ligand binding seems to be not sensitive of the P24T UGT1A4 polymorphism. This polymorphism is not located within a substrate binding site and does not impact on the effective dose of lamotrigine during the treatment of epilepsy. The data obtained in the study support this hypothesis.