RESUMEN
OBJECTIVES: Valproic acid (VPA)-induced adverse effects, which are sometimes serious in children, can be associated with alterations in VPA metabolism. VPA-evoked toxicity is attributed to both the parent compound and its unsaturated metabolites, primarily formed by the cytochrome P450 (CYP)2C9 enzyme. Thus, patients' CYP2C9-status may account for the predisposition to adverse reactions, and testing CYP2C9-status may contribute to the improvement and rationalization of VPA therapy in children. METHODS: In the CYPtest group, children's CYP2C9-status was screened before initiating antiepileptic therapy. CYP2C9-status was estimated by the identification of defective CYP2C9 allelic variants (CYP2C9*2, CYP2C9*3) and current CYP2C9 expression in patients' leukocytes, which reflects hepatic CYP2C9 activities. When the results of CYP2C9 genotyping and CYP2C9 expression were combined, the patients' VPA-metabolizing capacity was predicted, and VPA dosing was adjusted to the patients' CYP2C9-status. Clinical and biochemical parameters, such as VPA serum levels, blood cell counts, liver function parameters, and adverse effects in patients of CYPtest group were compared with those of the control group treated with VPA according to conventional clinical practice. RESULTS: CYP2C9-guided treatment significantly reduced VPA misdosing and consequently decreased the ratio of patients out of the range of target VPA blood concentrations. In the CYPtest group of children who received CYP2C9-status adapted dose, serum alkaline phosphatase (ALP) level and the ratio of patients with abnormal ALP levels were substantially lower than in the control group. The incidence of serious side effects, notably hyperammonemia, was reduced in the CYPtest group; however, some other side effects, such as weight changes and somnolence, could not be avoided. SIGNIFICANCE: The knowledge of pediatric patients' CYP2C9-status can contribute to the optimization of VPA dosing and to the avoidance of misdosing-induced side effects.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Citocromo P-450 CYP2C9/genética , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Farmacogenética , Ácido Valproico/uso terapéutico , Adolescente , Anticonvulsivantes/sangre , Niño , Preescolar , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Epilepsia/sangre , Femenino , Genotipo , Humanos , Lactante , Masculino , Ácido Valproico/sangreRESUMEN
BACKGROUND: Genetic polymorphisms of drug metabolizing enzymes can substantially modify the pharmacokinetics of a drug and eventually its efficacy or toxicity; however, inferring a patient's drug metabolizing capacity merely from his or her genotype can lead to false prediction. Non-genetic host factors (age, sex, disease states) and environmental factors (nutrition, comedication) can transiently alter the enzyme expression and activities resulting in genotypephenotype mismatch. Although valproic acid is a well-tolerated anticonvulsant, pediatric patients are particularly vulnerable to valproate injury that can be partly attributed to the age-related differences in metabolic pathways. METHODS: CYP2C9 mediated oxidation of valproate, which is the minor metabolic pathway in adults, appears to become the principal route in children. Genetic and non-genetic variations in CYP2C9 activity can result in significant inter- and intra-individual differences in valproate pharmacokinetics and valproate induced adverse reactions. RESULTS: The loss-of-function alleles, CYP2C9*2 or CYP2C9*3, display significant reduction in valproate metabolism in children; furthermore, low CYP2C9 expression in patients with CYP2C9*1/*1 genotype also leads to a decrease in valproate metabolizing capacity. Due to phenoconversion, the homozygous wild genotype, expected to be translated to CYP2C9 enzyme with normal activity, is transiently switched into poor (or extensive) metabolizer phenotype. CONCLUSION: Novel strategy for valproate therapy adjusted to CYP2C9-status (CYP2C9 genotype and CYP2C9 expression) is strongly recommended in childhood. The early knowledge of pediatric patients' CYP2C9-status facilitates the optimization of valproate dosing which contributes to the avoidance of misdosing induced adverse reactions, such as abnormal blood levels of ammonia and alkaline phosphatase, and improves the safety of children's anticonvulsant therapy.
Asunto(s)
Citocromo P-450 CYP2C9/metabolismo , Ácido Valproico/uso terapéutico , Adulto , Factores de Edad , Anticonvulsivantes/sangre , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapéutico , Vías Biosintéticas , Niño , Citocromo P-450 CYP2C9/genética , Epilepsia/tratamiento farmacológico , Epilepsia/metabolismo , Genotipo , Humanos , Fenotipo , Polimorfismo Genético , Ácido Valproico/sangre , Ácido Valproico/farmacocinéticaRESUMEN
AIM: Since prominent role in valproate metabolism is assigned to CYP2C9 in pediatric patients, the association between children's CYP2C9-status and serum valproate concentrations or dose-requirements was evaluated. MATERIALS & METHODS: The contribution of CYP2C9 genotype and CYP2C9 expression in children (n = 50, Caucasian) with epilepsy to valproate pharmacokinetics was analyzed. RESULTS: Valproate concentrations were significantly lower in normal expressers with CYP2C9*1/*1 than in low expressers or in patients carrying polymorphic CYP2C9 alleles. Consistently, the dose-requirement was substantially higher in normal expressers carrying CYP2C9*1/*1 (33.3 mg/kg vs 13.8-17.8 mg/kg, p < 0.0001). Low CYP2C9 expression significantly increased the ratio of poor metabolizers predictable from CYP2C9 genotype (by 46%). CONCLUSION: Due to the substantial downregulation of CYP2C9 expression in epilepsy, inferring patients' valproate metabolizing phenotype merely from CYP2C9 genotype results in false prediction.