Effects of CYP2C19 and CYP2C9 genotypes on pharmacokinetic variability of valproic acid in Chinese epileptic patients: nonlinear mixed-effect modeling

Jiang, Dechun; Bai, Xiangrong; Zhang, Qingxia; Lu, Wei; Wang, Yuqin; Li, Lin; Müller, Markus

doi:10.1007/s00228-009-0712-x

Cited by 50 publications

(47 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…There are at least three routes of VPA metabolism in humans: glucuronidation and β-oxidation in the mitochondria (both considered to be major routes accounting for 50% and 40% of the dose, respectively), and CYP-, such as CYP2C9 and CYP2C19, mediated-oxidation in the liver (considered to be a minor route, accounting for ∼10% of the dose) [24]. Similar to previous published population PK models for VPA [34]–[36], in the present study, a one-compartment model adequately described the VPA concentrations (Figure S1). …”

Section: Discussionsupporting

confidence: 61%

“…However, two other studies demonstrated an association between the CYP2C9 or CYP2C19 genotype and the PK parameters of VPA. Jiang et al reported that the CYP2C9 and CYP2C19 genotypes significantly influenced the population PK parameters of VPA in Chinese patients with epilepsy [34]. Tan et al indicated that subjects who were CYP2C9*3 allele carriers had higher mean plasma VPA concentrations than the non-carriers [38].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Impact of the Superoxide Dismutase 2 Val16Ala Polymorphism on the Relationship between Valproic Acid Exposure and Elevation of γ-Glutamyltransferase in Patients with Epilepsy: A Population Pharmacokinetic-Pharmacodynamic Analysis

et al. 2014

View full text Add to dashboard Cite

BackgroundThere has been accumulating evidence that there are associations among γ-glutamyltransferase (γ-GT) elevation and all-cause mortality, cardiovascular diseases and metabolic diseases, including nonalcoholic fatty liver disease. The primary objective of this study was to evaluate the impact of the most common and potentially functional polymorphisms of antioxidant enzyme genes, i.e. superoxide dismutase 2 (SOD2), glutathione S-transferase M1 and glutathione S-transferase T1, on the γ-GT elevation during valproic acid (VPA) therapy.Methods and FindingsThis retrospective study included 237 and 169 VPA-treated Japanese patients with epilepsy for population pharmacokinetic and pharmacokinetic-pharmacodynamic analyses, respectively. A nonlinear mixed-effect model represented the pharmacokinetics of VPA and the relationships between VPA exposure and γ-GT elevation. A one-compartment model of the pharmacokinetic parameters of VPA adequately described the data; while the model for the probability of the γ-GT elevation was fitted using a logistic regression model, in which the logit function of the probability was a linear function of VPA exposure. The SOD2 Val16Ala polymorphism and complication with intellectual disability were found to be significant covariates influencing the intercept of the logit function for the probability of an elevated γ-GT level. The predicted mean percentages of the subjects with γ-GT elevation were about 2- to 3-fold, 3- to 4-fold and 4- to 8-fold greater in patients with the SOD2 Val/Val genotype but without any intellectual disability, those with the SOD2 Val/Ala or Ala/Ala genotype and intellectual disability and those with the SOD2 Val/Val genotype and intellectual disability, respectively, compared to those with the SOD2 Val/Ala or Ala/Ala genotype without intellectual disability.ConclusionOur results showed that the SOD2 Val16Ala polymorphism has an impact on the relationship between VPA exposure and γ-GT elevation in patients with epilepsy. These results suggest that determining the SOD2 genotype could be helpful for preventing the VPA-induced γ-GT elevation.

show abstract

Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Impact of the Superoxide Dismutase 2 Val16Ala Polymorphism on the Relationship between Valproic Acid Exposure and Elevation of γ-Glutamyltransferase in Patients with Epilepsy: A Population Pharmacokinetic-Pharmacodynamic Analysis

et al. 2014

View full text Add to dashboard Cite

show abstract

“…A recent population pharmacokinetic study in 287 Chinese patients with epilepsy showed that CYP2C9 in combination with CYP2C19 genotypes significantly influenced the pharmacokinetic variability of valproic acid, as quantified by population pharmacokinetic analysis [120]. UGT2B7 also contributes to the glucuronidation of valproic acid [68,121].…”

Section: Effect Of Genetic Polymorphisms Of Drug-metabolizing Enzymentioning

confidence: 99%

Update on the Genetic Polymorphisms of Drug-Metabolizing Enzymes in Antiepileptic Drug Therapy

Saruwatari

Ishitsu²,

Nakagawa

2010

Pharmaceuticals

View full text Add to dashboard Cite

Genetic polymorphisms in the genes that encode drug-metabolizing enzymes are implicated in the inter-individual variability in the pharmacokinetics and pharmaco-dynamics of antiepileptic drugs (AEDs). However, the clinical impact of these polymorphisms on AED therapy still remains controversial. The defective alleles of cytochrome P450 (CYP) 2C9 and/or CYP2C19 could affect not only the pharmacokinetics, but also the pharmacodynamics of phenytoin therapy. CYP2C19 deficient genotypes were associated with the higher serum concentration of an active metabolite of clobazam, N-desmethylclobazam, and with the higher clinical efficacy of clobazam therapy than the other CYP2C19 genotypes. The defective alleles of CYP2C9 and/or CYP2C19 were also found to have clinically significant effects on the inter-individual variabilities in the population pharmacokinetics of phenobarbital, valproic acid and zonisamide. EPHX1 polymorphisms may be associated with the pharmacokinetics of carbamazepine and the risk of phenytoin-induced congenital malformations. Similarly, the UDP-glucuronosyltransferase 2B7 genotype may affect the pharmacokinetics of lamotrigine. Gluthatione S-transferase null genotypes are implicated in an increased risk of hepatotoxicity caused by carbamazepine and valproic acid. This article summarizes the state of research on the effects of mutations of drug-metabolizing enzymes on the pharmacokinetics and pharmacodynamics of AED therapies. Future directions for the dose-adjustment of AED are discussed.

show abstract

“…However, similar results were not achieved in other studies [41]. In addition, while there have been studies demonstrating the impact of CYP2C9 and/or CYP2C19 polymorphisms on VPA pharmacokinetics [28,42], other studies claimed no association between the CYP2C9 genotypes and VPA plasma concentrations or incidence of seizure [29,43,44]. We suppose such discrepancy lies in the fact that VPA is metabolized by multiple UGTs and CYPs, and the disposition could be related to other factors such as sample size, race, and patient age.…”

Section: Discussionmentioning

confidence: 56%

187 Early Post-Traumatic Seizures are Associated with Valproic Acid Plasma Concentrations and UGT1A6/CYP2C9 Genetic Polymorphisms in Patients with Severe Traumatic Brain Injury

Sun¹,

Yu²,

Yuan³

et al. 2017

Neurosurgery

View full text Add to dashboard Cite

show abstract

Effects of CYP2C19 and CYP2C9 genotypes on pharmacokinetic variability of valproic acid in Chinese epileptic patients: nonlinear mixed-effect modeling

Abstract: The CYP2C19 and CYP2C9 genotypes significantly influenced the PK variability of VPA, as quantified by NONMEM software.

Cited by 50 publications

References 30 publications

Impact of the Superoxide Dismutase 2 Val16Ala Polymorphism on the Relationship between Valproic Acid Exposure and Elevation of γ-Glutamyltransferase in Patients with Epilepsy: A Population Pharmacokinetic-Pharmacodynamic Analysis

Impact of the Superoxide Dismutase 2 Val16Ala Polymorphism on the Relationship between Valproic Acid Exposure and Elevation of γ-Glutamyltransferase in Patients with Epilepsy: A Population Pharmacokinetic-Pharmacodynamic Analysis

Update on the Genetic Polymorphisms of Drug-Metabolizing Enzymes in Antiepileptic Drug Therapy

187 Early Post-Traumatic Seizures are Associated with Valproic Acid Plasma Concentrations and UGT1A6/CYP2C9 Genetic Polymorphisms in Patients with Severe Traumatic Brain Injury

Contact Info

Product

Resources

About