Procyshyn Ric M, Ho Tiffany, Wasan Kishor M
Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
Drug Dev Ind Pharm. 2005 Oct;31(9):901-5. doi: 10.1080/03639040500272058.
To assess whether dyslipidemia affects haloperidol's overall plasma distribution when it is in the presence of another highly protein bound drug that competes for plasma protein binding sites.
We performed in vitro studies in which warfarin sodium was pre-incubated in normolipidemic and hyperlipidemic plasma samples in varying concentrations. Following the pre-incubation with warfarin, [3H]-haloperidol mixed with unlabeled haloperidol was added to the plasma samples. The plasma was separated into its lipoprotein and lipoprotein deficient fractions by density gradient ultracentrifugation and haloperidol distribution was determined.
Our results indicate that when normolipidemic plasma was pre-incubated with various concentrations of warfarin no significant redistribution of haloperidol was noted among the various plasma lipoprotein fractions. However, in the case of the hyperlipidemic plasma, pre-incubating with warfarin did result in a significant redistribution of haloperidol from the lipoprotein-deficient fraction to the very-low-density and low-density fractions of lipoproteins.
Understanding how plasma lipoproteins influence competitive displacement interactions would be valuable in helping to explain and perhaps predict pharmacokinetic parameters that may affect clinical outcome. The clinical significance of competitive displacement of drugs in patients with dyslipidemia requires further study.
评估在存在另一种竞争血浆蛋白结合位点的高蛋白结合药物时，血脂异常是否会影响氟哌啶醇的整体血浆分布。
我们进行了体外研究，将华法林钠在不同浓度的正常血脂和高脂血症血浆样本中进行预孵育。在与华法林预孵育后，将[3H] - 氟哌啶醇与未标记的氟哌啶醇混合加入血浆样本中。通过密度梯度超速离心将血浆分离为脂蛋白和脂蛋白缺乏部分，并测定氟哌啶醇的分布。
我们的结果表明，当正常血脂血浆与不同浓度的华法林预孵育时，在各种血浆脂蛋白部分中未观察到氟哌啶醇的显著重新分布。然而，在高脂血症血浆的情况下，与华法林预孵育确实导致氟哌啶醇从脂蛋白缺乏部分显著重新分布到极低密度和低密度脂蛋白部分。
了解血浆脂蛋白如何影响竞争性置换相互作用，对于帮助解释甚至预测可能影响临床结果的药代动力学参数将是有价值的。血脂异常患者中药物竞争性置换的临床意义需要进一步研究。
