Kazuyuki Inoue1, Toshiki Takahashi1, Yoshiaki Yamamoto2, Eri Suzuki1, Yukitoshi Takahashi2, Katsumi Imai2, Yushi Inoue2, Keita Hirai1, Daiki Tsuji1, Kunihiko Itoh3. 1. Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan. 2. Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Aoi-ku, Shizuoka City, Shizuoka 420-8688, Japan. 3. 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.
Abstract
PURPOSE: 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. CONCLUSION: 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.
PURPOSE: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 GLULrs10797771 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. CONCLUSION:Phenytoin coadministration, GLULrs10797771 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: Pavla Pokorná; Karolina Hronová; Martin Šíma; Ondřej Slanař; Petr Klement; John N van den Anker; Dick Tibboel Journal: Eur J Clin Pharmacol Date: 2017-02-06 Impact factor: 2.953