DECODING THE GENOME: CYP3A5 rs15524 POLYMORPHISM AND HOW IT AFFECTS PLASMA CARBAMAZEPINE LEVELS IN PATIENTS WITH EPILEPSY IN KHYBER PAKHTUNKHWA

Main Article Content

Ayesha Jamil
Niaz Ali
Muhammad Saleh Faisal
Gulmakay Zaman
Muhammad Sami Khan

Keywords

Single nucleotide polymorphism, CYP3A5, Epilepsy, Carbamazepine, Sanger sequencing

Abstract

Epilepsy is an unusually prevalent and intricated neurological condition afflicting millions of individuals globally. Carbamazepine (CBZ), one of the very important anti-epileptic drugs is metabolized by several enzymes, including CYP3A5, to produce its active metabolite, carbamazepine 10–11 epoxide. The extremely polymorphic CYP3A5 gene encodes for an extensive variety of metabolic substrates. Variability between patients in the pharmacokinetics of CBZ is indicative of metabolic differences. The prevalence of the single nucleotide polymorphism CYP3A5 (rs15524) and the study of the pharmacokinetic parameters of CBZ in the context of gene polymorphism among the Pashtun ethnic group of Khyber Pakhtunkhwa remains vacant. Nevertheless, this study examined the impact of genotypes of rs15524 on the CBZ pharmacokinetic variables.


Methods: A total of 223 patients were genotyped for CYP3A5 (rs15524) employing Sanger sequencing. Finch TV was used for the identification of gene polymorphisms, and HPLC explored their impact on plasma levels of CBZ.


Results: In CYP3A5 rs15524, the prevalence of wild genotype AA ref was 65.9%, heterozygous AG genotype was 29.1%, and homozygous mutant GG genotype was 4.9%. The values observed were in line with Hardy Weinberg equation. Generalized tonic clonic (GTC) seizure was the most prevalent type. Maximum GTC was recorded among AA ref carriers in an age range of 21-30 years. Maximum doses of CBZ were utilized by heterozygous AG carriers across both follow-ups with an uplift of 175.38±264.36 mg/day in the 2nd follow-up. The association between CYP3A5 rs15524 and doses utilized, was statistically significant (p-value-<0.001). Carriers of AA ref indicated the highest plasma levels of CBZ and CDR across both follow-ups. There was an uplift of 0.74±2.49 mg/l and a drop of 0.50±1.70 mg/l per mg/kg/day of plasma levels and CDR, respectively among AAref genotype in the 2nd follow-up. Statistically strong association between genotypes and plasma levels and CDR of CBZ was established.


Conclusion: Genotypes of the selected gene revealed a statistically significant association with CBZ pharmacokinetics.

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