Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia.
Sci Rep. 2023 Jan 23;13(1):1266. doi: 10.1038/s41598-023-28434-1.
Binding of therapeutics to proteins in blood plasma is important in influencing their distribution as it is their free (unbound) form that is able to cross cellular membranes to enter tissues and exert their actions. The concentration and composition of plasma proteins vary during pregnancy and development, resulting in potential changes to drug protein binding. Here, we describe an ultrafiltration method to investigate the extent of protein binding of six drugs (digoxin, paracetamol, olanzapine, ivacaftor, valproate and lamotrigine) and two water soluble inert markers (sucrose and glycerol) to plasma proteins from pregnant and developing rats. Results showed that the free fraction of most drugs was lower in the non-pregnant adult plasma where protein concentration is the highest. However, plasma of equivalent protein concentration to younger pups obtained by diluting adult plasma did not always exhibit the same extent of drug binding, reinforcing the likelihood that both concentration and composition of proteins in plasma influence drug binding. Comparison between protein binding and brain drug accumulation in vivo revealed a correlation for some drugs, but not others. Results suggests that plasma protein concentration should be considered when using medications in pregnant and paediatric patients to minimise potential for fetal and neonatal drug exposure.
药物与血浆蛋白的结合在影响其分布中起着重要作用，因为只有游离（未结合）形式的药物才能穿过细胞膜进入组织并发挥作用。血浆蛋白的浓度和组成在怀孕期间和发育过程中会发生变化，从而导致药物与蛋白的结合可能发生变化。在这里，我们描述了一种超滤方法，用于研究 6 种药物（地高辛、对乙酰氨基酚、奥氮平、依伐卡托、丙戊酸和拉莫三嗪）和 2 种水溶性惰性标志物（蔗糖和甘油）与来自怀孕和发育中的大鼠的血浆蛋白结合的程度。结果表明，大多数药物的游离分数在非妊娠成年期血浆中较低，因为此时蛋白浓度最高。然而，通过稀释成年期血浆获得的与幼崽具有相同蛋白浓度的血浆并不总是表现出相同的药物结合程度，这进一步证实了血浆中蛋白的浓度和组成都可能影响药物的结合。体内药物结合与脑内药物蓄积的比较显示，一些药物存在相关性，但其他药物则没有。结果表明，在孕妇和儿科患者中使用药物时应考虑血浆蛋白浓度，以尽量减少胎儿和新生儿暴露于药物的潜在风险。
