Effects of EPHX1, SCN1A and CYP3A4 genetic polymorphisms on plasma carbamazepine concentrations and pharmacoresistance in Chinese patients with epilepsy

Yun, Wenting; Zhang, Feng; Hu, Cheng; Luo, Xi; Xue, Peng; Wang, Jing; Meng, Hongmei; Guo, Yingjie

doi:10.1016/j.eplepsyres.2013.09.011

Cited by 30 publications

(27 citation statements)

References 26 publications

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“…These controversial results may be attributable to differences in substrate, ethnic background and cohort size. Several studies have reported that the EPHX1 c.337T>C or c.416A>G variants may be related to CDR CBZ [16,33]. However, no similar results were derived in our study.…”

Section: Discussioncontrasting

confidence: 79%

“…Tables 3, 4 & 5, and their genotype frequencies complied with Hardy-Weinberg equilibrium (p > 0.05). The genotype distribution frequencies of such SNPs except the EPHX1 c.128G>C were consistent with other studies on Chinese populations [13,16,24,33]. The frequency of the EPHX1 128C allele was 3.33% in Chinese patients with epilepsy.…”

Section: Quantitation Of Cbz and Its Major Metabolitessupporting

confidence: 88%

“…However, a study by Zhang et al has failed to find an association between the CYP3A4*1G polymorphism and cyclosporine trough concentrations in Chinese renal transplant recipients [15]. Moreover, a small size study has indicated that CYP3A4*1G had no effect on adjusted CBZ concentrations in Chinese patients with epilepsy [16]. Whether the CYP3A4*1G variant affects CBZ metabolism needs to be re-evaluated in a larger cohort.…”

Section: Introductionmentioning

confidence: 96%

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Effects of Major Transporter and Metabolizing Enzyme Gene Polymorphisms on Carbamazepine Metabolism in Chinese Patients with Epilepsy

et al. 2014

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Section: Discussioncontrasting

confidence: 79%

Section: Quantitation Of Cbz and Its Major Metabolitessupporting

confidence: 88%

Section: Introductionmentioning

confidence: 96%

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Effects of Major Transporter and Metabolizing Enzyme Gene Polymorphisms on Carbamazepine Metabolism in Chinese Patients with Epilepsy

et al. 2014

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“…Moreover, there was no association between these SNP genetic haplotypes and drug resistance, contrasted with previous studies that showed an association of these genotypes with response to AEDs. 18,19 CYP3A5 rs15524 was found to be related to the metabolism of the AEDs such as tacrolimus and carbamazepine; 20,36,37 however, there is a lack of data regarding its association with epilepsy. Emich-Widera et al failed to confirm the association of CYP3A5 polymorphism with drug resistance in Caucasian children with epilepsy.…”

Section: Discussionmentioning

confidence: 99%

“…[16][17][18] Moreover, 95% of the CBZ is metabolized by the liver; CYP3A4 and CYP3A5 are the most common enzymes that convert CBZ to CBZ-10, 11-epoxide (CBZ-E) in the major pathway of CBZ metabolism. 19 CYP3A5 along with 888 other enzymes belongs to the CYP enzymes that encoded by 57 human genes, including zinc finger protein 498 (ZNF498) whose products are involved mainly in oxidative drug metabolism. 20,21 Zinc finger proteins are of the mostly abundant proteins in the eukaryotic.…”

Section: Introductionmentioning

confidence: 99%

<p>Genetic polymorphisms of CYP3A5, CHRM2, and ZNF498 and their association with epilepsy susceptibility: a pharmacogenetic and case–control study</p>

AL-Eitan

Al-Dalalah

Mustafa

et al. 2019

PGPM

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Background: A total of 50 million persons were diagnosed worldwide with epilepsy. Onethird of them are experiencing debilitating seizures despite optimum anti-epileptic drugs (AEDs) treatment. Several studies have suggested that CYP3A5, CHRM2, and ZNF498 influence the pharmacokinetics of AEDs. Therefore, the severity of the disease as well as the degree of response to the AEDs could be affected by the genetic polymorphisms within these genes.Objectives: In this study, we assessed the effect of certain single nucleotide polymorphisms (SNPs) within CYP3A5, CHRM2, and ZNF498 genes on the susceptibility to develop epilepsy and the responsiveness to AEDs treatment. Methods: A case-control and pharmacogenetic study was conducted on samples of 299 healthy individuals in addition to 296 epileptic patients. Genotypic, allelic, and clinical data association were performed for the selected polymorphisms within the (rs324649, rs420817, rs15524, and rs1859690) in the Jordanian population. Results: The analysis revealed no significant association of the investigated SNPs with epilepsy in general, partial and generalized epilepsy as well as drug responsiveness. CYP3A5 and ZNF498 were associated with family history (P=0.003 and P=0.002, respectively) and the classification of epilepsy for the ZNF498 variant (P=0.009). On the other hand, CHRM2 was not linked to either disease severity or treatment responsiveness. Conclusion: Our results failed to confirm the association of CYP3A5, ZNF498, and CHRM2 variants with either disease development or treatment response. Clinical pharmacogenetic studies may contribute to treatment personalization, appropriate drug dose selection, minimizing drug adverse reactions, increasing drug efficacy, and reducing the costive burdens.

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Pharmacogenetic Variants and Plasma Concentrations of Antiseizure Drugs

Milosavljević,

Manojlović,

Matković

et al. 2024

JAMA Netw Open

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ImportancePrecise estimation of a patient’s drug metabolism capacity is important for antiseizure dose personalization.ObjectiveTo quantify the differences in plasma concentrations for antiseizure drugs associated with variants of genes encoding drug metabolizing enzymes.Data SourcesPubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to September 30, 2023, without language restrictions.Study SelectionTwo reviewers performed independent study screening and assessed the following inclusion criteria: appropriate genotyping was performed, genotype-based categorization into subgroups was possible, and each subgroup contained at least 3 participants.Data Extraction and SynthesisThe Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for data extraction and subsequent quality, validity, and risk-of-bias assessments. The results from the included studies were pooled with random-effect meta-analysis.Main Outcomes and MeasuresPlasma concentrations of antiseizure drugs were quantified with the dose-normalized area under the concentration-time curve, the dose-normalized steady state concentration, or the concentrations after a single dose at standardized dose and sampling time. The ratio of the means was calculated by dividing the mean drug plasma concentrations of carriers and noncarriers of the pharmacogenetic variant.ResultsData from 98 studies involving 12 543 adult participants treated with phenytoin, valproate, lamotrigine, or carbamazepine were analyzed. Studies were mainly conducted within East Asian (69 studies) or White or European (15 studies) cohorts. Significant increases of plasma concentrations compared with the reference subgroup were observed for phenytoin, by 46% (95% CI, 33%-61%) in CYP2C9 intermediate metabolizers, 20% (95% CI, 17%-30%) in CYP2C19 intermediate metabolizers, and 39% (95% CI, 24%-56%) in CYP2C19 poor metabolizers; for valproate, by 12% (95% CI, 4%-20%) in CYP2C9 intermediate metabolizers, 12% (95% CI, 2%-24%) in CYP2C19 intermediate metabolizers, and 20% (95% CI, 2%-41%) in CYP2C19 poor metabolizers; and for carbamazepine, by 12% (95% CI, 3%-22%) in CYP3A5 poor metabolizers.Conclusions and RelevanceThis systematic review and meta-analysis found that CYP2C9 and CYP2C19 genotypes encoding low enzymatic capacity were associated with a clinically relevant increase in phenytoin plasma concentrations, several pharmacogenetic variants were associated with statistically significant but only marginally clinically relevant changes in valproate and carbamazepine plasma concentrations, and numerous pharmacogenetic variants were not associated with statistically significant differences in plasma concentrations of antiseizure drugs.

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Effects of EPHX1, SCN1A and CYP3A4 genetic polymorphisms on plasma carbamazepine concentrations and pharmacoresistance in Chinese patients with epilepsy

Cited by 30 publications

References 26 publications

Effects of Major Transporter and Metabolizing Enzyme Gene Polymorphisms on Carbamazepine Metabolism in Chinese Patients with Epilepsy

Effects of Major Transporter and Metabolizing Enzyme Gene Polymorphisms on Carbamazepine Metabolism in Chinese Patients with Epilepsy

<p>Genetic polymorphisms of CYP3A5, CHRM2, and ZNF498 and their association with epilepsy susceptibility: a pharmacogenetic and case–control study</p>

Pharmacogenetic Variants and Plasma Concentrations of Antiseizure Drugs

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