Influence of EPHX1 c.337 T>C and UGT2B7*2 genetic polymorphisms on the requirement of carbamazepine maintenance dose in persons with epilepsy (PWE) of Southern part of India: a cross-sectional genetic association study

Abstract

Objectives Carbamazepine (CBZ) is a first-line antiseizure drug used for focal onset seizures. It exhibits inter-individual variability in plasma carbamazepine levels and there are both genetic and non-genetic factors having a role in the requirement of CBZ maintenance dose. The aim was to study the influence of EPHX1 c.337 T>C and UGT2B7*2 genetic polymorphisms on CBZ maintenance dose requirement in persons with epilepsy. Methods Persons with epilepsy (PWE) of both gender of age 15–65 years on carbamazepine monotherapy who had been taking same maintenance dose for one year were eligible. Five milliliter of venous blood was collected in 10% EDTA under aseptic precautions. After centrifugation, the cellular component was used for DNA extraction and genotyping. For three genotypes of EPHX1 c.337 T>C and UGT2B7*2, the differences in mean carbamazepine dose were analyzed using Analysis of Variance (ANOVA). An unpaired t-test was used to draw a comparison between the genotypes and CBZ maintenance dose requirement for dominant and recessive models of EPHX1 c.337 T>C and UGT2B7*2. A value of p<0.05 was considered to be statistically significant. Results For UGT2B7*2 (rs 7439366), CT required a higher dose (CT 626 mg/day and TT 523 mg/day) but not found to be significant (p-value 0.167). PWE carrying CT genotype of EPHX1 c.337 T>C had 62 mg higher dose when compared to homozygous mutant CC (590 mg/day for CT and 528 mg/day for CC) but p-value was not found to be significant (p-value 0.835). Conclusions The results of our study done in 115 PWE showed there was a lack of association between SNPs of EPHX1 c.337 T>C, UGT2B7*2 and CBZ maintenance dose requirement in Southern part of India and this finding has to be confirmed in a larger sample size.

Pharmacology of Connexins-Still a Gap

“…23 It is well documented that genetic factors play a significant role in the modulation of anti-seizures medications efficacy, adverse effects, and dose changes such as phenytoin, carbamazepine, sodium valproate. 24,25 Enhanced gap junctional communication (GJC) between neurons is considered a major factor underlying the neuronal synchrony driving seizure activity. In drug-resistant epilepsy, connexins, as integral components of gap junctions, are implicated in several key processes contributing to the resistance to antiepileptic drugs (AEDs).…”

Carbamazepine and Bipolar Disorder: Pharmacodynamics, Pharmacokinetics, Pharmacogenomics, and Adverse Drug Reactions- A Comprehensive Review

“…(b) Histidine to arginine conversion on exon 4 increases the enzyme activity (Venkatraman et al, 2023).…”

Genetic polymorphisms of microsomal epoxide hydrolase and UDP-glucuronosyltransferase (UGT) and its effects on plasma carbamazepine levels and metabolic ratio in persons with epilepsy of South India

“…[ 7 8 ] In South India, the minor allele frequencies of EPHX1 c. 337 T > C and UGT2B7*2 were 40%. [ 9 ] We reported that these genetic polymorphisms did not affect CBZ maintenance dose in South India,[ 10 ] and the impact of these genetic variants on the plasma CBZ levels and metabolic ratio is to be studied in PWE from South India for optimization of the drug therapy.…”