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Localized Disruption of Blood Albumin-Phenytoin Binding Using Transcranial Focused Ultrasound.
Ultrasound in Medicine & Biology ( IF 2.4 ) Pub Date : 2020-05-10 , DOI: 10.1016/j.ultrasmedbio.2020.04.011
Linda Xu 1 , Wonhye Lee 1 , Alexander Rotenberg 2 , Mark Böhlke 3 , Kyungho Yoon 1 , Seung-Schik Yoo 1
Affiliation  

Plasma protein binding (PPB) plays an important role in drug pharmacokinetics, particularly for central nervous system drugs, as PPB affects the blood concentration of unbound drug available to cross the blood–brain barrier (BBB). We report the non-invasive, spatially specific disruption of PPB to phenytoin, an anti-epileptic drug with high affinity to albumin, using 250-kHz focused ultrasound (FUS) delivered in a pulsed manner (55-ms tone burst duration, 4-Hz pulse repetitions). Equilibrium dialysis performed on sonicated phosphate-buffered saline solution containing phenytoin and bovine serum albumin revealed a 27.7% elevation in the unbound phenytoin concentration compared with an unsonicated control. Sonication of a unilateral brain hemisphere in rats (n = 10) after intraperitoneal phenytoin injection revealed increased parenchymal phenytoin uptake compared with the unsonicated hemisphere, without evidence of temperature change or BBB disruption. These findings illustrate the use of FUS as a novel technique for spatially selective disruption of PPB, which may be applied to a wide range of drug–plasma protein interactions.



中文翻译:

使用经颅聚焦超声局部破坏血白蛋白-苯妥英结合。

血浆蛋白结合 (PPB) 在药物药代动力学中起着重要作用,特别是对于中枢神经系统药物,因为 PPB 会影响可穿过血脑屏障 (BBB) 的未结合药物的血液浓度。我们报告了 PPB 对苯妥英的非侵入性、空间特异性破坏,苯妥英是一种对白蛋白具有高亲和力的抗癫痫药物,使用以脉冲方式传递的 250 kHz 聚焦超声 (FUS)(55 毫秒音调突发持续时间,4- Hz 脉冲重复)。对含有苯妥英和牛血清白蛋白的经超声处理的磷酸盐缓冲盐水溶液进行的平衡透析显示,与未经超声处理的对照相比,未结合的苯妥英浓度升高了 27.7%。腹腔内苯妥英注射后对大鼠(n = 10)单侧脑半球进行超声处理,显示与未超声处理的半球相比,实质苯妥英吸收增加,没有温度变化或 BBB 中断的证据。这些发现说明 FUS 作为一种新技术用于 PPB 的空间选择性破坏,可应用于广泛的药​​物 - 血浆蛋白质相互作用。

更新日期:2020-06-25
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