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

Caruso, Antonietta; Bellia, Chiara; Pivetti, Alessia; Agnello, Luisa; Bazza, Federica; Scazzone, Concetta; Bivona, Giulia; Sasso, Bruna Lo; Ciaccio, Marcello
April 2014
Pharmacogenomics & Personalized Medicine;2014, Vol. 7, p117
Academic Journal
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.


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