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. 2014 Apr 2:7:117-20.
doi: 10.2147/PGPM.S55548. eCollection 2014.

Effects of EPHX1 and CYP3A4 polymorphisms on carbamazepine metabolism in epileptic patients

Antonietta Caruso  1 , Chiara Bellia  1 , Alessia Pivetti  1 , Luisa Agnello  1 , Federica Bazza  1 , Concetta Scazzone  1 , Giulia Bivona  1 , Bruna Lo Sasso  1 , Marcello Ciaccio  1
Affiliations

Effects of EPHX1 and CYP3A4 polymorphisms on carbamazepine metabolism in epileptic patients

Antonietta Caruso et al. Pharmgenomics Pers Med. .

Abstract

Background: The aim of this study was to investigate the effect of two genetic polymorphisms in the coding regions (exon 3 and exon 4) of the EPHX1 gene, ie, 337T>C and 416A>G, respectively, on the metabolism of carbamazepine (CBZ) 10,11-epoxide (the active metabolite of CBZ) by evaluating the variation in serum CBZ 10,11-epoxide levels 4 hours after administration of the drug. Moreover, we reported the genotype frequencies of the CYP3A4*22 (rs 35599367, C>T) variant and its influence on the metabolism of CBZ.

Methods: The analysis was performed in 50 patients receiving CBZ as monotherapy. DNA was extracted from leukocytes using a commercially available kit. Serum CBZ 10,11-epoxide levels were measured by high-performance liquid chromatography. Allelic discrimination was performed using polymerase chain reaction-restriction fragment length polymorphism. Statistical analysis of the difference in mean values for CBZ 10,11-epoxide levels according to genotype was performed using the Student's t-test with Statistical Package for the Social Sciences version 13 software.

Results: Fourteen percent of the study group were CC, 42% were CT, and 44% were TT for the EPHX1 337T>C variant. No GG homozygote was identified for the EPHX1 416A>G variant; 64% were AA and 36% were AG. When we compared serum CBZ 10,11-epoxide levels 4 hours after drug administration, we found no statistically significant difference between the 337 CC, CT, and TT genotypes. Similarly, no difference in serum CBZ 10,11-epoxide levels was found between 416A>G AA and AG. Genotype frequencies for the CYP3A4*22 (rs 35599367 C>T) allelic variant were 94% for CC and 6% for CT, with no statistically significant difference in serum CBZ 10,11-epoxide levels between these genotypes 4 hours after administration of the drug (2.6±1.3 μg/μL and 2.5±1.2 μg/μL, respectively).

Conclusion: Although there is some evidence of involvement of these polymorphisms in enzyme activity in vitro, we found no interference with CBZ metabolism in vivo.

Keywords: 11-epoxide; CBZ 10; CYP3A4*22; EPHX1 gene; drug metabolism.

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