Significant dissociation of brain and plasma kinetics with antipsychotics
Significant dissociation of brain and plasma kinetics with antipsychotics
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DOI：
10.1038/sj.mp.4001009
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发表时间：
2002-01-01
影响因子：
11
通讯作者：
Kapur, S
中科院分区：
文献类型：
--
作者：
Tauscher, J;Jones, C;Kapur, S
目前精神药物的给药方案是基于血浆动力学考虑，尽管尚不清楚血浆水平是否忠实地反映了药物的大脑动力学。(1,2) 为了检验这一点，我们比较了两种广泛使用的抗精神病药物奥氮平和利培酮的血浆水平动力学及其在大脑中作用的时间过程。我们使用正电子发射断层扫描 (PET) 和 [C-11] 标记配体来量化健康受试者和长期接受精神病治疗的患者在单次给药后的纹状体和纹状体外多巴胺 2 (D-2) 和皮质 5-羟色胺 2A (5-HT2A) 受体的占用情况。我们发现大脑和血浆动力学存在显着的分离。单剂量奥氮平和利培酮的平均血浆消除半衰期分别为 24.2 和 10.3 小时，而奥氮平平均需要 75.2 小时，利培酮平均需要 66.6 小时才能降至纹状体 D-2 受体占用峰值的 50%。我们发现血浆水平和纹状体外 D-2 以及 5-HT2A 受体占用的时间进程之间存在类似的差异。我们的结果对目前依赖血浆动力学作为抗精神病药物给药方案的主要依据提出了质疑。脑动力学研究可能为确定精神药物的给药方案提供更可靠的基础。
Current dosing regimens of psychotropic drugs are based on plasma kinetic considerations, although it is unclear whether plasma levels faithfully reflect brain kinetics of drugs.(1,2) To examine this, we compared the kinetics of plasma levels of two widely used antipsychotics, olanzapine and risperidone, vs the time course of their effects in the brain. We used positron emission tomography (PET) and [C-11]-labeled ligands to quantify striatal and extra-striatal dopamine-2 (D-2), and cortical serotonin-2A (5-HT2A) receptor occupancy in healthy subjects after a single dose, and in patients chronically treated for psychosis. We found a significant dissociation of brain and plasma kinetics. Mean plasma elimination half-lives of single doses of olanzapine and risperidone were 24.2 and 10.3 h, respectively, whereas it took on average 75.2 h with olanzapine, and 66.6 h with risperidone to decline to 50% of their peak striatal D-2 receptor occupancy. We found similar discrepancies between the time course of plasma levels and extra-striatal D-2 as well as 5-HT2A receptor occupancy. Our results question the current reliance on plasma kinetics as the main basis for dosing regimens of antipsychotics. Studies of brain kinetics may provide a sounder basis for determining dosing schedules of psychotropic medications.