Association of Polymorphisms in
 EPHX1
 ,
 UGT2B7
 ,
 ABCB1
 ,
 ABCC2
 ,
 SCN1A
 and
 SCN2A
 Genes with Carbamazepine Therapy Optimization

Hung, Chin‐Chuan; Chang, Wei-Lun; Ho, Jia-Ling; Tai, John Jen; Hsieh, Tsung-Jen; Huang, Hsiao‐Ching; Hsieh, Ying‐Hen; Liou, Horng-Huei

doi:10.2217/pgs.11.141

Cited by 68 publications

(50 citation statements)

References 50 publications

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“…In another study of 234 Chinese epileptic patients under maintenance CBZ monotherapy SCN1A IVS5-91G > A was revealed to be significantly associated with CBZ dosages and concentration-dose ratios (CDRs). Furthermore, a multiple regression model demonstrated that genetic variants in SCN1A, EPHX1 and UGT2B7 genes were interactively associated with the CDRs of CBZ [42]. A similar investigation also demonstrated that carriers of the variant SCN1A IVS5-91G > A and EPHX1 c.337T > C allele tended to require higher CBZ dosages and lower CDRs than non-carriers (p < 0.0001) [42].…”

Section: Drug Targetsmentioning

confidence: 81%

“…Previously, a significant association of EPHX1 SNPs with the maintenance dose of CBZ [r(2) = 0.362, p = 0.002] had also been reported [65]. In a recent work, the same EPHX1 allele patient carriers tended to require higher CBZ dosages and lower concentrationdose ratios than non-carriers [42]. A diplotype analysis of 416A > G (His193Arg) and Tyr113His SNPs showed increased plasma CBZ-diol/CBZ-E ratios in vivo in Japanese epilepsy patients, and also both SNPs were demonstrated to alter the enzymatic expression levels and activity both in vitro and in vivo [38].…”

Section: Pharmacogenetics Of Carbamazepine Metabolismmentioning

confidence: 87%

“…Furthermore, a multiple regression model demonstrated that genetic variants in SCN1A, EPHX1 and UGT2B7 genes were interactively associated with the CDRs of CBZ [42]. A similar investigation also demonstrated that carriers of the variant SCN1A IVS5-91G > A and EPHX1 c.337T > C allele tended to require higher CBZ dosages and lower CDRs than non-carriers (p < 0.0001) [42]. Additionally, a significant difference was found in the retention rates of CBZ with respect to the rs3812718 A/G polymorphism of the SCN1A gene throughout 24 months of clinical follow-up (p=0.038) in 448 Chinese patients with epilepsy [54].…”

Section: Drug Targetsmentioning

confidence: 99%

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Pharmacogenetic potential biomarkers for carbamazepine adverse drug reactions and clinical response

Monroy-Jaramillo

Fricke-Galindo

Vázquez

et al. 2014

Drug Metabolism and Drug Interactions

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Carbamazepine (CBZ) is a first-line widely used anticonvulsant. It has a narrow therapeutic index and exhibits considerable interindividual and interethnic variability in clinical efficacy and adverse drug reactions including potentially life-threatening hypersensitivity reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. The most important pharmacogenetic finding is related to the association of CBZ-induced hypersensitivity with human leukocyte antigens (HLA class I and II alleles). Moreover, genotyping for HLA-B*15:02 allele is required prior to initiating CBZ in Asians and Asian ancestry patients, demonstrating the usefulness of biomarkers to avoid adverse drug reactions. On the other hand, in order to explain the differences in the clinical response to CBZ, genetic polymorphisms in phase I (CYP3A4, CYP3A5 and EPHX1) and phase II (UGT2B7) metabolising enzymes have been assessed; additionally, the influence of transporters (ABCB1 and ABCC2), receptors (PXR) and other drug targets (voltage- gated Na+ channels) in CBZ clinical response has been evaluated. To date, these studies are controversial and require further investigations to clarify the functional role of these polymorphisms as potential biomarkers in regard to CBZ therapy.

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Section: Drug Targetsmentioning

confidence: 81%

Section: Pharmacogenetics Of Carbamazepine Metabolismmentioning

confidence: 87%

Section: Drug Targetsmentioning

confidence: 99%

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Pharmacogenetic potential biomarkers for carbamazepine adverse drug reactions and clinical response

Monroy-Jaramillo

Fricke-Galindo

Vázquez

et al. 2014

Drug Metabolism and Drug Interactions

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“…n Genotyping As for PHT pharmacokinetic-and pharmacodynamic-related genes, it is known that several variants in SCN1A, SCN2A, CYP2C9, CYP2C19, ABCB1 and ABCC2 genes would affect the basic expression or function of the target protein [5][6][7][8][9][10][11][12]19,20,22,24,44]. Although UGT1A1 is the enzyme responsible for the conjugation of the PHT oxidative metabolites [45], the activity of UGT1A1 has not been reported to be relevant to PHT concentrations.…”

Section: Methodsmentioning

confidence: 99%

“…However, the association between SCN1A IVS5-91G>A and maximum dose of carbamazepine was not detected in other replication studies [21][22][23]. The gene encoded the isoform of α-subunit of Nav1.2, SCN2A, was reported to be associated with epilepsy treatment response [24,25]; therefore, may affect the dosage requirement of PHT therapy.…”

mentioning

confidence: 95%

Effects of Polymorphisms in Six Candidate Genes on Phenytoin Maintenance Therapy in Han Chinese Patients

et al. 2012

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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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Association of Polymorphisms in EPHX1 , UGT2B7 , ABCB1 , ABCC2 , SCN1A and SCN2A Genes with Carbamazepine Therapy Optimization

Abstract: The present study identified genetic factors associated with CBZ therapy optimization and provided useful information for individualized CBZ therapy in epileptic patients. Further studies in larger populations are needed to confirm our results.

Cited by 68 publications

References 50 publications

Pharmacogenetic potential biomarkers for carbamazepine adverse drug reactions and clinical response

Pharmacogenetic potential biomarkers for carbamazepine adverse drug reactions and clinical response

Effects of Polymorphisms in Six Candidate Genes on Phenytoin Maintenance Therapy in Han Chinese Patients

Pharmacogenetic Variants and Plasma Concentrations of Antiseizure Drugs

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