Dosage Recommendation of Phenytoin for Patients with Epilepsy with Different CYP2C9/CYP2C19 Polymorphisms

Hung, Chin‐Chuan; Lin, Chun-Jung; Chen, Chih-Chuan; Chang, Chee‐Jen; Liou, Horng-Huei

doi:10.1097/00007691-200410000-00012

Cited by 103 publications

(86 citation statements)

References 14 publications

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“…However, it seems to be clear that several factors may contribute to the lack of correlation between CYP2C9 genetic polymorphism and PAR. Not only CYP2C9 but also CYP2C19 has been reported to catalyze phenytoin 8,14 . Some studies also indicate the role of P-glycoprotein in the disposition of phenytoin.…”

Section: Frequency (%)mentioning

confidence: 99%

“…Genetic variation in the CYP2C9 gene can affect metabolism, leading to altered phenotypes. Individuals with poor metaboliser alleles of CYP2C9 gene were shown to have a reduced metabolism of phenobarbital, phenytoin and valproate compared with those with wild-type (normal) alleles [2][3][4][5][6][7][8][9] . Several studies indicate that the most common allelic variants are Arg 144 Cys (CYP2C9*2) and Ile 358 Leu (CYP2C9*3) which encode enzymes with decreased substrate turnover 10,11 .…”

mentioning

confidence: 99%

“…Its main rout of elimination is through hepatic oxidation under CYP2C9 (90%) and CYP2C19 (10%) metabolism 8,14,15 . Phenytoin metabolism rate can be reduced by 25 to 50 % depending on the individual genetic polymorphism and drug interactions through same pathway 2,8,14,16 . Its use can be associated to several dose related or idiosyncratic adverse events.…”

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confidence: 99%

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

Twardowschy

Werneck

Scola

et al. 2011

Arq. Neuro-Psiquiatr.

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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

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Section: Frequency (%)mentioning

confidence: 99%

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confidence: 99%

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

Twardowschy

Werneck

Scola

et al. 2011

Arq. Neuro-Psiquiatr.

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“…First, the initial association between polymorphism in genes for the PHT metabolizing enzyme CYP2C9 and pharmacokinetic parameters of PHT treatment 5,6 has been confirmed. 7 More recent studies provide additional confirmation of influence of CYP2C9 genotype on PHT treatment by showing that patients harboring the *3 allele exhibit a modest (10-15%) but significant reduction in maximum tolerated dose of PHT. 8 It is estimated that only a small portion (less than 10%) of the variance in the maximum tolerated dose of PHT was explained by polymorphism at the CYP2C9 locus.…”

Section: Impact Of Pharmacogenetics On Antiepileptic Drug Dosementioning

confidence: 91%

“…In another study, estimated daily doses required to keep PHT in the usual reference boundaries of 10-20 mg/l ranged from 2-3 to 5.5-7 mg/kg/day based on genotyping of polymorphisms in CYP2C9 and CYP2C19. 7 The other genetic factor putatively associated with AED treatment is SCN1A. 8 It represents the first strong association between a clinically relevant AED end point and a gene that encodes a therapeutic target for the AED and if confirmed could have a significant impact on treatment paradigms.…”

Section: Impact Of Pharmacogenetics On Antiepileptic Drug Dosementioning

confidence: 99%

Defining the clinical role of pharmacogenetics in antiepileptic drug therapy

2006

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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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Dosage Recommendation of Phenytoin for Patients with Epilepsy with Different CYP2C9/CYP2C19 Polymorphisms

Cited by 103 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

Defining the clinical role of pharmacogenetics in antiepileptic drug therapy

Pharmacogenetic Variants and Plasma Concentrations of Antiseizure Drugs

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