Effect Of UGT2B7 Gene Polymorphisms rs77439366 (C802T) On Serum Concentration Of Valproic Acidin The Iraqi Epileptic Patients

Abstract

Background Valproic acid (VPA) is commonly used to treat epilepsy in children. In the predominant pathway, it is metabolized by the uridine diphosphate glucuronosyl transferase 2B7 (UGT2B7) enzyme. UGT2B7 is a UGT isozyme that promotes carboxyl, hydroxyl, amino, and methoxyl glucuronidation and is a crucial metabolic enzyme that prevents the accumulation of potentially hazardous lipophilic chemicals and initiates their removal through the more hydrophilic biliary and renal systems. the effects of inheritable polymorphisms on human UGT-encoding genes has been well documented, and it has been shown to contribute for a fraction of the phenotypic heterogeneity in metabolism and excretion. in this study we seek to determine the effects of genetic variants in the UGT2B7 gene on serum VPA levels in steady-state condition among epileptic patients . UGT2B7 is agene on chromosome 4q13 16-kilobase gene with six exons. The proximal promoter region of this gene contains many polymorphisms. Exon 2 of UGT2B7 contains the C802T polymorphism , which is a common missense (MAF = 0.3349)
Aim. Investigated the relationship between serum VPA levels and UGT2B7 genotypes in order to determine how rs77439366C802Tvariation has impact on VPA pharmacokinetics.
Methodology Patients (n=113) were initially prescribed the ER formulations of valproate (Depakine Chrono) tablet and (depakine) syrup 10-15 mg/kg . The physician determined the dose,frequency of dosage, initial and maintenance doses, and any additional increases or decreased basis of their seizures control, serum VPA concentration was measured after three and six months of treatment in 103 ,90 patients,respectively.The dosing regimen was continued for at least 2 weeks (>5 half-lives) to maintain a steady-state condition with respect to drugs pharmacokinetics. serum VPA was measured by chemiluminescent microparticle immunoassay (CMIA) technology for the quantitative measurement of valproic acid in human serum in vitrowith a linear range of (2 -150 μg /mL). The UGT2B7rs77439366 (802C > T) in the coding regions were genotyped using polymerase chain reaction amplification .
Results After three and six months of regular valproic acid administration, patients with the T allele at UGT2B7 C802T had significantly lower adjusted VPA concentrations than those with the CC genotype.
Conclusion The findings suggested that UGT2B7 C802T may be an essential predictor of individual variability in VPA pharmacokinetics, and that individuals with the T allele may need to increase their VPA dose to achieve the therapeutic range of 50–100 μg /mL.