Department of Clinical & Experimental Epilepsy, NIHR University College London Hospitals Biomedical Research Centre, UCL Institute of Neurology, London, United Kingdom.
Chalfont Centre for Epilepsy, Chalfont St. Peter, United Kingdom.
Epilepsia. 2017 Jul;58(7):1234-1243. doi: 10.1111/epi.13802. Epub 2017 May 24.
Given that only the free non-protein-bound concentration of an antiepileptic drug (AED) crosses the blood-brain barrier, entering the brain and producing an antiepileptic effect, knowledge and measurement of the free drug fraction is important. Such data are sparse, particularly for newer AEDs, and have arisen from the use of disparate methodologies and settings over the past six decades. We report on the protein binding of 25 AEDs that are available for clinical use, along with two pharmacologically active metabolites (carbamazepine-epoxide and N-desmethyl clobazam), using standardized methodology and under set conditions.
The protein binding of the various AEDs was undertaken in sera of 278 patients with epilepsy. Separation of the free non-protein-bound component was achieved by using ultracentrifugation (Amicon Centrifree Micropartition System) under set conditions: 500 μl serum volume; centrifugation at 1,000 g for 15 min, and at 25°C. Free and total AED concentrations were measured by use of fully validated liquid chromatography/mass spectroscopy (LC/MS) techniques.
Gabapentin and pregabalin are non-protein-bound, whereas highly bound AEDs (≥88%) include clobazam, clonazepam, perampanel, retigabine, stiripentol, tiagabine, and valproic acid as well as the N-desmethyl-clobazam (89%) metabolite. The minimally bound drugs (<22%) include ethosuximide (21.8%), lacosamide (14.0%), levetiracetam (3.4%), topiramate, (19.5%) and vigabatrin (17.1%). Ten of the 25 AEDs exhibit moderate protein binding (mean range 27.7-74.8%).
These data provide a comprehensive comparison of serum protein binding of all available AEDs including the metabolites, carbamazepine-epoxide and N-desmethyl-clobazam. Knowledge of the free fraction of these AEDs can be used to optimize epilepsy treatment.
由于只有抗癫痫药物（AED）的游离非蛋白结合浓度能够穿过血脑屏障，进入大脑并产生抗癫痫作用，因此了解和测量游离药物部分非常重要。此类数据非常有限，尤其是对于较新的 AED，并且是过去六十年中使用不同方法和环境得出的。我们报告了 25 种可用于临床的 AED 以及两种具有药理活性的代谢物（卡马西平-环氧和 N-去甲基氯巴占）的蛋白结合情况，使用了标准化方法和设定的条件。
在 278 名癫痫患者的血清中进行了各种 AED 的蛋白结合研究。游离非蛋白结合成分的分离是通过在设定条件下使用超速离心（Amicon Centrifree Micropartition System）实现的：500μl 血清体积；在 25°C 下以 1,000g 离心 15min。游离和总 AED 浓度通过使用完全验证的液相色谱/质谱（LC/MS）技术进行测量。
加巴喷丁和普瑞巴林是非结合的，而高度结合的 AED（≥88%）包括氯巴占、氯硝西泮、帕瑞昔布、雷替加滨、司替戊醇、噻加宾和丙戊酸以及 N-去甲基-氯巴占（89%）代谢物。结合最低的药物（<22%）包括乙琥胺（21.8%）、拉科酰胺（14.0%）、左乙拉西坦（3.4%）、托吡酯（19.5%）和维加特林（17.1%）。25 种 AED 中有 10 种具有中等蛋白结合（平均范围 27.7-74.8%）。
这些数据提供了所有可用 AED 及其代谢物、卡马西平-环氧和 N-去甲基-氯巴占的血清蛋白结合的全面比较。了解这些 AED 的游离部分可以用于优化癫痫治疗。
