Effects ofEPHX1andCYP3A4*22genetic polymorphisms on carbamazepine metabolism and drug response among Tunisian epileptic patients

Abstract

The aim of this study was to evaluate the impact of polymorphisms in the EPHX1 (c.416A > G, c.337T > C) and CYP3A4*22 genes involved in carbamazepine (CBZ) metabolism and pharmacoresistance among 118 Tunisian patients with epilepsy under maintenance dose of CBZ. These genetic polymorphisms were analyzed by PCR-RFLP. Associations between plasma CBZ concentration, CBZ-E concentration, maintenance doses and metabolic ratio (CBZ-E:CBZ, CBZ-D:CBZ-E) were analyzed with each polymorphism. Both variants of EPHX1 c.416A > G and c.337T > C are significantly associated with higher metabolic ratio CBZ-E:CBZ and seem to decrease the activity of the epoxide hydrolase. The CYP3A4*22 variant allele is significantly associated with lower CBZ-D:CBZ-E ratio and seems also to be associated with less activity of the cytochrome. Our data suggest that certain polymorphisms of metabolizing enzyme genes could influence inter-individual variability of CBZ metabolism.

A genome‐wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine

“…Polymorphisms in CYP3A4 and EPHX1 have been shown to associate with interindividual variability of CBZ metabolism. 14,15 We did not observe even nominally significant associations between SNPs in CYP3A4 and CBZ metabolic ratio. It had been reported that homozygous carriers of the EPHX1 c.416A>G SNP (rs2234922) seemingly show a reduced CBZ metabolism, as measured by a significantly decreased metabolic ratio.…”

ABCB1 c.3435C>T and EPHX1 c.416A>G polymorphisms influence plasma carbamazepine concentration, metabolism and pharmacoresistance in epileptic patients

“…For EPHX1 c.416A>G polymorphism, the adjusted concentrations of CDR CBZ , CDR CBZE and CDR CBZD were reported in 4 [7,8,25,31], 3 [7,8,31] and 3 [7,8,31] articles, respectively. A total of 646 epilepsy patients treated by CBZ in 3 studies were included with statistically significant association between (AA vs GG) ,(AG vs GG) models in EPHX1 c.416A>Gpolymorphisms and CDR CBZD (OR = 0.483 (95% CI: 0.011˜0.956), P = 0.045; OR = 0.682 (95% CI: 0.163˜1.201), P = 0.010, respectively) (Table 3) (Fig.…”

“…For EPHX1 c.337T>C polymorphisms, the adjusted concentrations of CDR CBZ , CDR CBZE , CDR CBZD , CDR CBZE : CDR CBZ and CDR CBZD : CDR CBZE including 812 epilepsy patients were reported in 4 [7,8,25,31], 3 [7,8,31], 3 [7,8,31], 3 [7,8,17] and 3 [7,8,31] articles, respectively. A statistically significant association was found in the (TT vs CC) model for the adjusted concentrations of CDR CBZE (OR = -0.446 (95% CI: -0.811˜-0.0.081), P = 0.004) with high heterogeneity (I 2 =98.9%) (Table 3).…”

“…The search criteria on PubMed, Web of Knowledge and Cochrane databases yielded 932 hits of which 324 were duplicates. After removal of additional 590 records (including one [21] of the two articles [21,22] with the same sample published in different journals was excluded), 13 studies of CBZ resistance [7,8,13,14,[22][23][24][25][26][27][28][29][30] and 8 studies of CBZ metabolism [7,8,17,25,29,[31][32][33] were included in the systematic review (Fig. 1).…”

“…Subsequently, CBZE inactivated to carbamazepine-10,11-transdihydrodiol (CBZD) by microsomal epoxide hydrolase which is encoded by microsomal epoxide hydrolase (EPHX1 ) [6]. Meanwhile, the genetic variants ofc.337T>C (rs1051740) and c.416A>G (rs2234922) in EPHX1 were found associated with the pharmacokinetics and pharmacodynamics of CBZ [7,8]. P-glycoprotein (P-gp), producted by ATP binding cassette transporter, subfamily B, member 1 (ABCB1 ) or multidrug resistance 1 gene (MDR1 ), is a highly reported drug efflux transporter as CBZ substrates [9][10][11].…”