Inoue Kazuyuki, Takahashi Toshiki, Yamamoto Yoshiaki, Suzuki Eri, Takahashi Yukitoshi, Imai Katsumi, Inoue Yushi, Hirai Keita, Tsuji Daiki, Itoh Kunihiko
Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan.
Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Aoi-ku, Shizuoka City, Shizuoka 420-8688, Japan.
Seizure. 2015 Dec;33:76-80. doi: 10.1016/j.seizure.2015.10.015. Epub 2015 Nov 6.
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.
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.
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.
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.
丙戊酸（VPA）被广泛用于治疗癫痫、偏头痛和双相情感障碍，但可导致严重的高氨血症。然而，这种不良反应的机制尚不清楚。我们之前报道过，在基于VPA的治疗过程中，合用苯妥英是发生高氨血症的一个重要危险因素。在本研究中，我们聚焦于谷氨酰胺合成酶，其催化谷氨酸和氨合成谷氨酰胺，并研究了其与基于VPA的治疗过程中高氨血症发生的相关性。
在本研究中，我们招募了202例日本癫痫患儿。我们选择了谷氨酰胺合成酶（GLUL）基因中的三个多态性位点（rs10911070、rs10797771和rs10911021）。高氨血症定义为血浆氨水平超过200或170μg/dL。我们评估了基于VPA的治疗过程中高氨血症的发生与患者特征之间的相关性，包括三个GLUL多态性位点。
以200μg/dL为临界值时，在基于VPA的治疗过程中发生高氨血症的患者有20例（9.9%）；以170μg/dL为临界值时，有30例（14.9%）。采用多因素逻辑回归分析，在200μg/dL临界值时，GLUL rs10797771多态性位点及合用苯妥英，以及在170μg/dL临界值时除这两个因素外的女性因素，均与基于VPA的治疗过程中血浆氨水平升高显著相关。
合用苯妥英、在200μg/dL临界值时的GLUL rs10797771多态性位点，以及在170μg/dL临界值时除这两个因素外的女性因素，是基于VPA的治疗过程中血浆氨水平升高的独立危险因素。
