Abstract | BACKGROUND: METHODS AND FINDINGS: This 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. CONCLUSION: Our 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.
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Authors | Naoki Ogusu, Junji Saruwatari, Hiroo Nakashima, Madoka Noai, Miki Nishimura, Mariko Deguchi, Kentaro Oniki, Norio Yasui-Furukori, Sunao Kaneko, Takateru Ishitsu, Kazuko Nakagaswa |
Journal | PloS one
(PLoS One)
Vol. 9
Issue 11
Pg. e111066
( 2014)
ISSN: 1932-6203 [Electronic] United States |
PMID | 25372290
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Anticonvulsants
- Valproic Acid
- Superoxide Dismutase
- superoxide dismutase 2
- gamma-Glutamyltransferase
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Topics |
- Adolescent
- Adult
- Algorithms
- Amino Acid Substitution
- Anticonvulsants
(pharmacokinetics, therapeutic use)
- Child
- Child, Preschool
- Epilepsy
(diagnosis, drug therapy, genetics, metabolism)
- Female
- Genotype
- Humans
- Male
- Middle Aged
- Models, Biological
- Pharmacogenetics
- Polymorphism, Genetic
- Retrospective Studies
- Superoxide Dismutase
(genetics)
- Valproic Acid
(pharmacokinetics, therapeutic use)
- Young Adult
- gamma-Glutamyltransferase
(blood, metabolism)
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