Title:Relevance of CYP2C9 Function in Valproate Therapy
VOLUME: 17 ISSUE: 1
Author(s):Katalin Monostory*, Andrea Nagy, Katalin Tóth, Tamás Bűdi , Ádám Kiss, Máté Déri and Gábor Csukly
Affiliation:Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Heim Pal Children's Hospital, Budapest, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, 2nd Department of Pediatrics, Semmelweis University, Budapest, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest
Keywords:Valproic acid, epilepsy, psychiatric disorders, CYP2C9 genotype, CYP2C9 expression, personalized medication,
pediatric patients.
Abstract: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.