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

Abstract

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

Pediatric perspective on pharmacogenomics

“…Specifically, carriers of the variant CYP2C9*3 tended to require significantly lower maintenance phenytoin dosages (p < 0.0001) and generated significantly higher concentration-dose ratios than wild-type carriers (p < 0.004) [139]. This was not, however, confirmed in a separate study [140].…”

Pharmacogenomics research and clinical implementation in Brazil

“…Figure shows a flowchart of our search results. After filtering PubMed entries and publications from REFARGEN members, 72 articles were selected, 22 of which examined both pharmacogene(s) and drug(s) from a CPIC guideline (Table ). The remaining 50 articles investigated one or more genes comprised in the guidelines.…”

“…One study examined the impact of CYP2C9*2 and *3 genotypes on phenytoin adverse reactions and failed to detect an association, possibly because of the small size of the study cohort and the fact that most patients were receiving co‐medications . In a small subset of the same cohort, the authors observed a significant reduction in cerebellar white matter volume in carriers of CYP2C9 variants compared to wild‐type patients .…”

Pharmacogenetics of drug metabolizing enzymes in Brazilian populations

“…An early report of the group described no association of the studied polymorphisms ( with phenytoin dosage or ADRs [52], however the authors performed a further study with the same study group using imaging data to assess cerebellar atrophy signs and showed a reduction in cerebellar volume related to *2/*3 allele carriers [53].…”