Phenoconversion of CYP2C9 in epilepsy limits the predictive value of CYP2C9 genotype in optimizing valproate therapy. (June 2015)

• Record Type: Journal Article
• Authors: Tóth, Katalin; Bűdi, Tamás; Kiss, Ádám; Temesvári, Manna; Háfra, Edit; Nagy, Andrea; Szever, Zsuzsa; Monostory, Katalin
• Is Part Of: Personalized medicine. Volume 12:Number 3(Year 2015)
• Page Start: 199
• Page End: 207
• Publication Date: 2015-06
• Subjects: CYP2C9 expression -- CYP2C9 genotype -- CYPtest -- cytochrome P450 -- epilepsy -- pediatric patients -- personalized medication -- valproate therapy; Pharmacogenomics -- Periodicals; Pharmacogenetics -- Periodicals; 615.19
• DOI: 10.2217/pme.14.82
• Languages: English
• ISSNs: 1741-0541

Abstract

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.