RESUMO
We aimed to explore the possible influence of CYP2C9 (*2, *3 and IVS8-109 A>T), CYP2C19 (*2, *3 and *17) and ABCB1 (1236C>T, 2677G>A/T and 3435C>T) on phenytoin (PHT) plasma concentrations in 64 Mexican Mestizo (MM) patients with epilepsy currently treated with PHT in mono- (n=25) and polytherapy (n=39). Genotype and allele frequencies of these variants were also estimated in 300 MM healthy volunteers. Linear regression models were used to assess associations between the dependent variables (PHT plasma concentration and dose-corrected PHT concentration) with independent variables (CYP2C9, CYP2C19 and ABCB1 genotypes, ABCB1 haplotypes, age, sex, weight, and polytherapy). In multivariate models, CYP2C9 IVS8-109 T was significantly associated with higher PHT plasma concentrations (t(64)=2.27; P=0.03). Moreover, this allele was more frequent in the supratherapeutic group as compared with the subtherapeutic group (0.13 versus 0.03, respectively; P=0.05, Fisher's exact test). Results suggest that CYP2C9 IVS8-109 T allele may decrease CYP2C9 enzymatic activity on PHT. More research is needed to confirm findings.
Assuntos
Anticonvulsivantes/sangue , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9/genética , Epilepsia/tratamento farmacológico , Epilepsia/genética , Variantes Farmacogenômicos/genética , Fenitoína/sangue , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Adolescente , Adulto , Idoso , Anticonvulsivantes/administração & dosagem , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Monitoramento de Medicamentos , Epilepsia/sangue , Epilepsia/etnologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Modelos Lineares , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Análise Multivariada , Fenótipo , Fenitoína/administração & dosagem , Fatores de Risco , Resultado do Tratamento , Adulto JovemRESUMO
AIM: Different patients exhibit wide variability in the way they respond to medications. Individual differences in drug response can result from environmental factors, as well as genetic determinants. In particular, inherited differences in the metabolism and disposition of drugs can have a great influence on the efficacy and toxicity of medications, so herein we focus on the pharmacogenetics of drug metabolism. DEVELOPMENT: Clinical observations of inherited differences in drug effects were first documented in the 1950s, giving rise to the field of pharmacogenetics. These observations were then followed by population studies of drug disposition phenotype, then biochemical, and eventually molecular elucidation of the genetic defect associated with the inherited trait. Genetic polymorphisms have been described for many phase I and phase II drug-metabolizing enzymes including several cytochromes P450, N-acetyltransferases, and thiopurine S-methyltransferase. Rapid advances in human genomics gave birth to pharmacogenomics, an emerging discipline that uses genome-wide approaches to study the entire spectrum of genes involved in drug response. High-through-put genomic technologies will serve as the foundation of personalized therapies. CONCLUSIONS: Knowledge of an individual's genetic variability in drug response may be clinically and economically important and could provide the basis for a rational approach to drug prescription in neuropsychiatric disorders.