Preclinical tissue distribution and metabolic correlations of vigabatrin, an antiepileptic drug associated with potential use-limiting visual field defects
Preclinical tissue distribution and metabolic correlations of vigabatrin, an antiepileptic drug associated with potential use-limiting visual field defects
复制标题
DOI：
10.1002/prp2.456
复制
发表时间：
2019-02-01
影响因子：
2.6
通讯作者：
Gibson, K. M.
中科院分区：
文献类型：
--
作者：
Walters, Dana C.;Jansen, Erwin E. W.;Gibson, K. M.
Vigabatrin(vgb；(S)-(+)/(-)4-氨基六-5-烯酸)是一种抗癫痫药，不可逆灭活γ-氨基丁酸转氨酶(GABA-T)，具有限用眼毒性。假设Vgb的活性S对映体优先在眼和视皮层蓄积是眼毒性的一个潜在机制，我们以35、70和140 mg/kg/d(n=6-8只动物/剂量)的小鼠皮下注射外消旋vgb，持续12天。用质谱法测定眼、脑、肝、前额叶和Vc的Vgb对映体、总GABA和β-丙氨酸(BALA)、4-GBA(4-GBA)和肌酸。血浆vgb浓度随剂量的增加呈线性增加(3+/-0.76(35 mg/kg/d)；15.1+/-1.4(70 mg/kg/d)；34.6+/-3.2MU/L(140 mg/kg/d)；平均+/-扫描电子显微镜(Mean+/-SEM)，S/受体比值为0.74+/-0.02(n=14)。稳态S/R比值(35、70 mg/kg/d)以眼(5.5±-0.2；P<；0.0001)最高，其次为VC(3.9+/-0.4)、PFC(3.6+/-0.3)、肝脏(2.9+/-0.1)和脑(1.5+/-0.1；n=13~14)。各剂量组眼组织总VGB含量均高于脑、PFC和Vc。大剂量VGB可减少内源性代谢物的产生，尤其是在PFC和Vc。GABA在除脑外的所有组织中均显著升高，Bala升高仅限于肝脏和Vc，4-GBA在脑、PFC和Vc(和高剂量眼)中显著升高。在所有组织中，对映体与GABA均呈线性相关，但仅在Bala、4-GBA和肌酸的PFC/VC中呈线性相关。Vgb S异构体在眼内和视网膜区的优先蓄积可能为研究vgb的眼毒性提供新的视角。
Vigabatrin (VGB; (S)-(+)/(R)-(-) 4-aminohex-5-enoic acid), an antiepileptic irreversibly inactivating GABA transaminase (GABA-T), manifests use-limiting ocular toxicity. Hypothesizing that the active S enantiomer of VGB would preferentially accumulate in eye and visual cortex (VC) as one potential mechanism for ocular toxicity, we infused racemic VGB into mice via subcutaneous minipump at 35, 70, and 140 mg/ kg/d (n = 6-8 animals/dose) for 12 days. VGB enantiomers, total GABA and beta-alanine (BALA), 4-guanidinobutyrate (4-GBA), and creatine were quantified by mass spectrometry in eye, brain, liver, prefrontal cortex (PFC), and VC. Plasma VGB concentrations increased linearly by dose (3 +/- 0.76 (35 mg/kg/d); 15.1 +/- 1.4 (70 mg/kg/d); 34.6 +/- 3.2 mu mol/L (140 mg/kg/d); mean +/- SEM) with an S/R ratio of 0.74 +/- 0.02 (n = 14). Steady state S/R ratios (35, 70 mg/kg/d doses) were highest in eye (5.5 +/- 0.2; P < 0.0001), followed by VC (3.9 +/- 0.4), PFC (3.6 +/- 0.3), liver (2.9 +/- 0.1), and brain (1.5 +/- 0.1; n = 13-14 each). Total VGB content of eye exceeded that of brain, PFC and VC at all doses. High-dose VGB diminished endogenous metabolite production, especially in PFC and VC. GABA significantly increased in all tissues (all doses) except brain; BALA increases were confined to liver and VC; and 4-GBA was prominently increased in brain, PFC and VC (and eye at high dose). Linear correlations between enantiomers and GABA were observed in all tissues, but only in PFC/ VC for BALA, 4-GBA, and creatine. Preferential accumulation of the VGB S isomer in eye and VC may provide new insight into VGB ocular toxicity.