Relevance of CYP2C9 Function in Valproate Therapy

BACKGROUND: Genetic polymorphisms of drug metabolizing enzymes can substantially modify the pharmacokinet-ics 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, co-medication) can transiently alter the enzyme expression and activities resulting in genotype-phenotype mis-match. Although valproic acid is a well-tolerated anticonvulsant, pediatric patients are particularly vulnerable to valproate in-jury 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 en-zyme 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 lev-els of ammonia and alkaline phosphatase, and improves the safety of children’s anticonvulsant therapy.