Abstract | AIM: The present study aimed to evaluate the effects of gene variants in key genes influencing pharmacokinetic and pharmacodynamic of carbamazepine (CBZ) on the response in patients with epilepsy. MATERIALS & METHODS: Five SNPs in two candidate genes influencing CBZ transport and metabolism, namely ABCB1 or EPHX1, and CBZ response SCN1A ( sodium channel) were genotyped in 145 epileptic patients treated with CBZ as monotherapy and 100 age and sex matched healthy controls. Plasma concentrations of CBZ, carbamazepine-10,11-epoxide (CBZE) and carbamazepine-10,11-trans dihydrodiol ( CBZD) were determined by HPLC-UV-DAD and adjusted for CBZ dosage/kg of body weight. RESULTS: The presence of the SCN1A IVS5-91G>A variant allele is associated with increased epilepsy susceptibility. Furthermore, carriers of the SCN1A IVS5-91G>A variant or of EPHX1 c.337T>C variant presented significantly lower levels of plasma CBZ compared to carriers of the common alleles (0.71 ± 0.28 vs 1.11±0.69 μg/mL per mg/Kg for SCN1A IVS5-91 AA vs GG and 0.76 ± 0.16 vs 0.94 ± 0.49 μg/mL per mg/Kg for EPHX1 c.337 CC vs TT; P<0.05 for both). Carriers of the EPHX1 c.416A>G showed a reduced microsomal epoxide hydrolase activity as reflected by a significantly decreased ratio of CBZD to CBZ (0.13 ± 0.08 to 0.26 ± 0.17, p<0.05) also of CBZD to CBZE (1.74 ± 1.06 to 3.08 ± 2.90; P<0.05) and CDRCBZD (0.13 ± 0.08 vs 0.24 ± 0.19 μg/mL per mg/Kg; P<0.05). ABCB1 3455C>T SNP and SCN1A 3148A>G variants were not associated with significant changes in CBZ pharmacokinetic. Patients resistant to CBZ treatment showed increased dosage of CBZ (657 ± 285 vs 489 ± 231 mg/day; P<0.001) but also increased plasma levels of CBZ (9.84 ± 4.37 vs 7.41 ± 3.43 μg/mL; P<0.001) compared to patients responsive to CBZ treatment. CBZ resistance was not related to any of the SNPs investigated. CONCLUSIONS: The SCN1A IVS5-91G>A SNP is associated with susceptibility to epilepsy. SNPs in EPHX1 gene are influencing CBZ metabolism and disposition. CBZ plasma levels are not an indicator of resistance to the therapy.
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Authors | Armond Daci, Giangiacomo Beretta, Driton Vllasaliu, Aida Shala, Valbona Govori, Giuseppe Danilo Norata, Shaip Krasniqi |
Journal | PloS one
(PLoS One)
Vol. 10
Issue 11
Pg. e0142408
( 2015)
ISSN: 1932-6203 [Electronic] United States |
PMID | 26555147
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Anticonvulsants
- NAV1.1 Voltage-Gated Sodium Channel
- SCN1A protein, human
- Carbamazepine
- Epoxide Hydrolases
- EPHX1 protein, human
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Topics |
- Adolescent
- Adult
- Albania
- Anticonvulsants
(blood, pharmacokinetics, therapeutic use)
- Carbamazepine
(blood, pharmacokinetics, therapeutic use)
- Chromatography, High Pressure Liquid
- Epilepsy
(drug therapy)
- Epoxide Hydrolases
(genetics)
- Ethnicity
(genetics)
- Female
- Humans
- Male
- Middle Aged
- NAV1.1 Voltage-Gated Sodium Channel
(genetics)
- Polymorphism, Single Nucleotide
- Spectrophotometry, Ultraviolet
- Young Adult
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