title: Influence of glutamine synthetase gene polymorphisms on the development of hyperammonemia during valproic acid-based therapy.
abstract: OBJECTIVE
  Valproic acid (VPA), which is widely used to treat epilepsy, migraine, and bipolar disorder, can causes severe hyperammonemia. However, the mechanism responsible for this adverse effect is not readily apparent. We previously reported that phenytoin coadministration is a strong risk factor for the development of hyperammonemia during VPA-based therapy. In this study, we focused on glutamine synthetase, which catalyzes the synthesis of glutamine from glutamate and ammonia and examined the association with the development of hyperammonemia during VPA-based therapy.
  
  
  METHODS
  For this study, we recruited 202 Japanese pediatric patients having epilepsy. We selected three polymorphisms (rs10911070, rs10797771, and rs10911021) in the glutamine synthetase (GLUL) gene. Hyperammonemia was defined as a plasma ammonia level exceeding 200 or 170 μg/dL. We evaluated the association between the development of hyperammonemia during VPA-based therapy and the patient characteristics, including three GLUL polymorphisms.
  
  
  RESULTS
  The number of patients who developed hyperammonemia during VPA-based therapy was 20 (9.9%) using the 200 μg/dL cutoff value and 30 (14.9%) using the 170 μg/dL cutoff value. Using a multivariate logistic regression analysis, the GLUL rs10797771 polymorphism and phenytoin coadministration in the 200 μg/dL cutoff value, and female in addition to two factors in the 170 μg/dL cutoff value, had significant associations with a plasma ammonia level elevation during VPA-based therapy.
  
  
  CONCLUSIONS
  Phenytoin coadministration, GLUL rs10797771 polymorphism in the 200μg/dL cutoff value, and female in addition to two factors in the 170μg/dL cutoff value, are independent risk factors for elevated plasma ammonia levels during VPA-based therapy.
authors.affiliation: Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Aoi-ku, Shizuoka City, Shizuoka 420-8688, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Suzuki
authors.affiliation: Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Aoi-ku, Shizuoka City, Shizuoka 420-8688, Japan.
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Aoi-ku, Shizuoka City, Shizuoka 420-8688, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Imai
authors.affiliation: Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Aoi-ku, Shizuoka City, Shizuoka 420-8688, Japan.
authors.forename: Yushi
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Hirai
authors.affiliation: Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Tsuji
authors.affiliation: Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan. Electronic address: itohk@u-shizuoka-ken.ac.jp.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Itoh
mesh_terms: D000293:Adolescent; D000641:Ammonia / Q000097:blood; D000927:Anticonvulsants / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics; D005260:Female; D005838:Genotype; D005974:Glutamate-Ammonia Ligase / Q000235:genetics*; D006801:Humans; D022124:Hyperammonemia / Q000139:chemically induced* / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D016015:Logistic Models; D008297:Male; D010672:Phenytoin / Q000009:adverse effects; D011110:Polymorphism, Genetic / Q000235:genetics*; D012737:Sex Factors; D014635:Valproic Acid / Q000009:adverse effects*
chemical_list: D000927:Anticonvulsants; D014635:Valproic Acid; D010672:Phenytoin; D000641:Ammonia; D005974:Glutamate-Ammonia Ligase
keywords: Epilepsy; Glutamine synthetase; Hyperammonemia; Polymorphism; Valproic acid