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 May;31(4-5):331-7. doi: 10.1081/ddc-54305.
This study assesses whether competitive displacement of clozapine by warfarin affects clozapine's overall plasma distribution.
Warfarin sodium was preincubated in normolipidemic and hyperlipidemic plasma samples in varying concentrations. Following the preincubation with warfarin, [3H]clozapine mixed with unlabeled clozapine was added to the plasma samples. The plasma was separated into its lipoprotein and lipoprotein-deficient fractions by density gradient ultracentrifugation, and clozapine distribution was determined.
When normolipidemic plasma was preincubated with various concentrations of warfarin, no significant redistribution of clozapine was noted among the various plasma lipoprotein fractions. However, in the case of the hyperlipidemic plasma, preincubating with warfarin did result in a significant redistribution of clozapine from the lipoprotein-deficient fraction to the very-low-density and low-density fractions of lipoproteins. Based on pharmacokinetic principles, the steady-state unbound concentration of clozapine in normolipidemic and hyperlipidemic plasma is not expected to change.
Although no change in the steady-state unbound (active) concentration of clozapine would predict no change in clinical status, it is possible that this may only apply to the individuals with a normal lipid profile. We believe clozapine's association with lipoproteins (particularly triglycerides) may actually increase clozapine's effectiveness.
本研究评估华法林对氯氮平的竞争性置换是否会影响氯氮平在血浆中的整体分布。
将不同浓度的华法林钠在正常血脂和高脂血症血浆样本中进行预孵育。在用华法林预孵育后，将与未标记氯氮平混合的[3H]氯氮平加入血浆样本中。通过密度梯度超速离心将血浆分离为脂蛋白和缺乏脂蛋白的部分，并测定氯氮平的分布。
当正常血脂血浆与不同浓度的华法林预孵育时，未观察到氯氮平在不同血浆脂蛋白部分之间有明显的重新分布。然而，在高脂血症血浆的情况下，用华法林预孵育确实导致氯氮平从缺乏脂蛋白的部分显著重新分布到极低密度和低密度脂蛋白部分。根据药代动力学原理，预计氯氮平在正常血脂和高脂血症血浆中的稳态游离浓度不会改变。
虽然氯氮平稳态游离（活性）浓度没有变化预示临床状态不会改变，但这可能仅适用于血脂正常的个体。我们认为氯氮平与脂蛋白（特别是甘油三酯）的结合实际上可能会提高氯氮平的疗效。
