CYP2C polymorphisms, phenytoin metabolism and gingival overgrowth in epileptic subjects

Soga, Yoshihiko; Nishimura, Fusanori; Ohtsuka, Yoko; Araki, Hiroaki; Iwamoto, Yoshihiro; Naruishi, Hisa; Shiomi, Nobuyuki; Kobayashi, Yoshitomo; Takashiba, Shogo; Shimizu, Kenji; Gomita, Yutaka; Oka, Eiji

doi:10.1016/j.lfs.2003.07.018

Cited by 66 publications

(49 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Also, topiramate, clobazam, primidone and valproic acid were used less frequently. present no CYP2C9*2 mutation and very low incidence of CYP2C9*3, ranging from 1.1 32 to 5.4 18 . These findings may imply that the CYP2C9 allele evolved quite recently.…”

Section: Resultsmentioning

confidence: 94%

“…In our study only 8% showed this adverse reaction. Subjects with more severe gingival overgrowth exhibited significantly higher serum phenytoin concentration, but the degree of gingival overgrowth did not directly correlate with CYP2C9 polymorphisms 18 . However, CYP2C9*3 variant could play a role in the proportion of patients with diphenylhydantoin induced cutaneous adverse reaction 20 .…”

Section: Frequency (%)mentioning

confidence: 82%

“…A few studies have tried to established a relationship between the development of phenytoin side effects and the presence of CYP2C9*2 and CYP2C9*3 variants 18,20 . Incidence of phenytoin induced gingival overgrowth in epileptic patients may be as high as 57% 19 , but whether this or other phenytoin side effects may be influenced by cytochrome P450 polymorphism remains to be yet determined.…”

Section: Frequency (%)mentioning

confidence: 99%

“…Neuronal toxic effects including confusion, dysarthric speech, double vision, ataxic gait and neuropathy could be observed during prolonged use or in acute intoxications 13 . Moreover, some studies have tried to link the development of those side effects looking for a correlation between CYP2C9 genetic polymorphism and phenytoin adverse reactions [18][19][20] . Interethnic differences in CYP2C9 allele distribution have been described between Europeans, Asiatics and Africans 1,21 .…”

mentioning

confidence: 99%

See 3 more Smart Citations

CYP2C9 polymorphism in patients with epilepsy: genotypic frequency analyzes andphenytoin adverse reactions correlation

Twardowschy

Werneck

Scola

et al. 2011

Arq. Neuro-Psiquiatr.

View full text Add to dashboard Cite

Objective: CYP2C9 is a major enzyme in human drug metabolism and the polymorphism observed in the corresponding gene may affect therapeutic outcome during treatment. The distribution of variant CYP2C9 alleles and prevalence of phenytoin adverse reactions were hereby investigated in a population of patients diagnosed with epilepsy. Method: Allele-specific PCR analysis was carried out in order to determine frequencies of the two most common variant alleles, CYP2C9*2 and CYP2C9*3 in genomic DNA isolated from 100 epileptic patients. We also analyzed the frequency of phenytoin adverse reactions among those different genotypes groups. The data was presented as mean±standard deviation. Results: The mean age at enrollment was 39.6±10.3 years (range, 17-72 years) and duration of epilepsy was 26.5±11.9 years (range 3-48 years). The mean age at epilepsy onset was 13.1±12.4 years (range, 1 month-62 years). Frequencies of CYP2C9*1 (84%), CYP2C9*2 (9%) and CYP2C9*3 (7%) were similar to other published reports. Phenytoin adverse reactions were usually mild and occurred in 15% patients, without correlation with the CYP2C9 polymorphism (p=0.34). Conclusion: Our findings indicate an overall similar distribution of the CYP2C9 alleles in a population of patients diagnosed with epilepsy in the South of Brazil, compared to other samples. This sample of phenytoin users showed no drug related adverse reactions and CYP2C9 allele type correlation. The role of CYP2C9 polymorphism influence on phenytoin adverse reaction remains to be determined since some literature evidence and our data found negative results. Key words: CYP2C9, polymorphism, Brazilian population, phenytoin, adverse reactions.Polimorfismo do CYP2C9 em pacientes com epilepsia: estudo da frequência genotípica e correlação com os efeitos colaterais da fenitoína RESUMO Objetivo: A CYP2C9 é uma das principais enzimas do metabolismo de drogas humano e o polimorfismo observado no respectivo gene pode afetar o resultado terapêutico durante o tratamento. Neste trabalho investigamos em uma população de pacientes portadores de epilepsia a distribuição dos alelos variantes do CYP2C9 e a frequência de efeitos adversos da fenitoína tentando estabelecer uma correlação. Método: Realizamos uma análise através de uma PCR alelo específica para determinar a frequência dos alelos variantes mais comuns, CYP2C9*2 e CYP2C9*3, isolados da amostra de 100 pacientes com epilepsia. Também levantamos a frequência de reações adversas da fenitoína nestes diferentes grupos genotípicos. Os dados são apresentados na forma de média e desviopadrão. Resultados: A idade média na inclusão foi 39,6±10,3 anos (variando de 17-72 anos) e a duração da epilepsia era 26,5±11,9 anos (variando de 3-48 anos). A idade média dos pacientes no início da epilepsia era 13,1±12,4 anos (variando de 1 mês-62 anos). As frequências do CYP2C9*1 (84%), CYP2C9*2 (9%) e CYP2C9*3 (7%) foram similares Correspondence Carlos Silvado Hospital de Clínicas / UFPR Rua General Carneiro 181 / 3° andar 80060-900 Curitiba PR -Brasil

show abstract

Section: Resultsmentioning

confidence: 94%

Section: Frequency (%)mentioning

confidence: 82%

Section: Frequency (%)mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

CYP2C9 polymorphism in patients with epilepsy: genotypic frequency analyzes andphenytoin adverse reactions correlation

Twardowschy

Werneck

Scola

et al. 2011

Arq. Neuro-Psiquiatr.

View full text Add to dashboard Cite

show abstract

“…Studies have investigated the relationship between CYP2C9 and cutaneous 546 GARDINER AND BEGG reactions and gingival overgrowth (Soga et al, 2004). More individuals with the CYP2C9*1/*3 genotype were found among Korean patients with skin reactions to phenytoin compared with nonexposed controls (3 of 10 versus 1 of 169; crude odds ratio 71, p ϭ 0.001) .…”

Section: B Cyp2c9mentioning

confidence: 99%

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

2006

View full text Add to dashboard Cite

Pharmacogenetic Variants and Plasma Concentrations of Antiseizure Drugs

Milosavljević,

Manojlović,

Matković

et al. 2024

JAMA Netw Open

View full text Add to dashboard Cite

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.

show abstract

CYP2C polymorphisms, phenytoin metabolism and gingival overgrowth in epileptic subjects

Cited by 66 publications

References 14 publications

CYP2C9 polymorphism in patients with epilepsy: genotypic frequency analyzes andphenytoin adverse reactions correlation

CYP2C9 polymorphism in patients with epilepsy: genotypic frequency analyzes andphenytoin adverse reactions correlation

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

Pharmacogenetic Variants and Plasma Concentrations of Antiseizure Drugs

Contact Info

Product

Resources

About