Distribution pattern of UGT1A6 and UGT2B7 gene polymorphism and its impact on the pharmacokinetics of valproic acid and carbamazepine: Prospective genetic association study conducted in Pakistani patients with epilepsy

Abstract

Background: Ethnic variation is one of the important factors in clinical practice that may affect the pharmacokinetics of drugs. The present study aims to determine the distribution pattern of UGT1A6 and UGT2B7 gene polymorphism and its possible impact on the metabolism of valproic acid (VPA) and carbamazepine (CBZ) in patients with epilepsy from Khyber Pakhtunkhwa region of Pakistan.

Methods: After the enrollment of targeted patients, blood was collected for genotype analysis through Sanger sequencing. Plasma concentrations of VPA and CBZ were determined by reversed-phase high-performance liquid chromatography (HPLC) at the follow-up visit of third month from the initiation of therapy. The drug plasma levels were correlated with different genotypes of UGT1A6 and UGT2B7 to determine the impact of genetic polymorphism on the drug metabolism.

Results: Of the total 178 epileptic patients, 120 subjects were prescribed VPA monotherapy while 58 subjects were given CBZ monotherapy. The mean age of the subjects was recorded as 26.1 ± 13.5 years with a predominance of the male gender. Generalized tonic-clonic (GTC) was the most prevalent type of seizure (82%) followed by partial seizure. Genotype analysis revealed that the frequency of homozygous and heterozygous variants of the targeted UGT genes were exceptionally high in the Khyber Pakhtunkhwa population compared to the ethnic groups of other countries. In UGT1A6-A552C and UGT1A6-A541G, AC and AG were the most prevalent genotypes with respective frequencies of 43.2% and 41.1% whereas, in UGT2B7-T161C and UGT2B7-G211T, TC and GG were the most prevalent genotypes with respective frequencies of 42.7% and 99.4%. In the VPA-treated group, the homozygous and heterozygous variants of UGT1A6-A552C and UGT1A6-A541G were significantly associated with lower drug plasma concentrations (p < 0.05). However, none of the genotypes of UGT2B7-T161C revealed any significant association with VPA plasma concentration (p greater than 0.05). In the CBZ-treated group, UGT gene polymorphisms were not recognized to cause alteration in the drug plasma concentrations (p greater than 0.05).

Conclusion: The genetic polymorphisms of UGT1A6, but not UGT2B7 significantly affected the plasma levels of valproic acid. The chosen SNPs did not reveal a role in determining the plasma levels of carbamazepine.

Keywords: Carbamazepine; Epilepsy; Sanger sequencing; UGT gene polymorphism; Valproic acid.