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.
BACKGROUND
There 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.


RESULTS
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.


CONCLUSIONS
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.
Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Naoki
N
Ogusu
Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Junji
J
Saruwatari
Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Hiroo
H
Nakashima
Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Madoka
M
Noai
Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Miki
M
Nishimura
Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Mariko
M
Deguchi
Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Kentaro
K
Oniki
Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan.
Norio
N
Yasui-Furukori
Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan.
Sunao
S
Kaneko
Kumamoto Saishunso National Hospital, Kumamoto, Japan; Kumamoto Ezuko Ryoiku Iryo Center, Kumamoto, Japan.
Takateru
T
Ishitsu
Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; Center for Clinical Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Kazuko
K
Nakagaswa
D000293:Adolescent; D000328:Adult; D000465:Algorithms; D019943:Amino Acid Substitution; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D013482:Superoxide Dismutase / Q000235:genetics*; D014635:Valproic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use; D055815:Young Adult; D005723:gamma-Glutamyltransferase / Q000097:blood / Q000378:metabolism*; D000099156:Superoxide Dismutase 2
D000927:Anticonvulsants; D013482:Superoxide Dismutase; D014635:Valproic Acid; D005723:gamma-Glutamyltransferase; D000099156:Superoxide Dismutase 2