Gidal Barry E, Ferry Jim, Laurenza Antonio, Ueno Takashi
School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705, USA.
Eisai Inc., Woodcliff Lake, NJ, 07677, USA.
Epilepsy Res. 2019 Jan;149:102-106. doi: 10.1016/j.eplepsyres.2018.12.003. Epub 2018 Dec 12.
Plasma protein binding and effects on volume of distribution and pharmacologically active, circulating-drug concentrations are complex issues. Protein-binding displacement often underlies drug-drug interactions. Perampanel is a once-daily oral anti-seizure drug for focal seizures and primary generalized tonic-clonic seizures. Perampanel is also indicated for monotherapy use for focal seizures in the United States. Perampanel is extensively but slowly metabolized via CYP3A4. Its elimination t is about 100 h, and it displays substantial plasma protein binding (>95%). Here, we examine perampanel's potential to displace highly bound anti-seizure drugs and the ability of warfarin, a standard highly protein-bound drug, to displace perampanel. Protein binding of perampanel, phenytoin, valproate, and warfarin was assessed using equilibrium dialysis. Plasma samples containing each compound were dialyzed against phosphate buffered saline. For phenytoin, valproate, and warfarin, plasma samples were also dialyzed in the presence of perampanel. After 24 h equilibrium dialysis, amounts of test compounds were analyzed to calculate plasma protein binding. At clinically relevant concentrations, perampanel did not displace other highly bound drugs or vice versa. Protein-binding displacement may confound therapeutic drug monitoring of extensively protein-bound medications. Without empirical data, clinicians might be concerned that addition of perampanel could alter unbound concentrations of other medications, resulting in adverse effects. Our data indicate perampanel has low potential for drug interactions resulting from protein-binding displacement.
血浆蛋白结合以及对分布容积和药理活性循环药物浓度的影响是复杂的问题。蛋白结合置换常常是药物相互作用的基础。吡仑帕奈是一种每日一次的口服抗癫痫药物，用于治疗局灶性癫痫发作和原发性全面性强直阵挛发作。在美国，吡仑帕奈也被批准用于局灶性癫痫发作的单药治疗。吡仑帕奈通过CYP3A4进行广泛但缓慢的代谢。其消除半衰期约为100小时，并且显示出较高的血浆蛋白结合率（>95%）。在此，我们研究了吡仑帕奈置换高度结合的抗癫痫药物的可能性，以及标准的高度蛋白结合药物华法林置换吡仑帕奈的能力。使用平衡透析法评估了吡仑帕奈、苯妥英、丙戊酸盐和华法林的蛋白结合情况。将含有每种化合物的血浆样本与磷酸盐缓冲盐水进行透析。对于苯妥英、丙戊酸盐和华法林，血浆样本也在吡仑帕奈存在的情况下进行透析。经过24小时的平衡透析后，分析测试化合物的量以计算血浆蛋白结合率。在临床相关浓度下，吡仑帕奈不会置换其他高度结合的药物，反之亦然。蛋白结合置换可能会混淆对广泛蛋白结合药物的治疗药物监测。如果没有经验数据，临床医生可能会担心添加吡仑帕奈会改变其他药物的游离浓度，从而导致不良反应。我们的数据表明，吡仑帕奈因蛋白结合置换导致药物相互作用的可能性较低。
