In vitro P-glycoprotein affinity for atypical and conventional antipsychotics
In vitro P-glycoprotein affinity for atypical and conventional antipsychotics
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DOI：
10.1016/s0024-3205(02)01680-6
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发表时间：
2002-05-31
期刊：
影响因子：
6.1
通讯作者：
Markowitz, JS
中科院分区：
文献类型：
--
作者：
Boulton, DW;DeVane, CL;Markowitz, JS
跨膜转运体P-糖蛋白(P-gp)是一种依赖于ATP的药物外排泵。P-gp潜在地限制了对精神活性底物脑组织的获取，但对其抗精神病药物的特异性知之甚少。本研究的目的是评估一些非典型抗精神病药物在体外对P-gp的亲和力，以表明它们在体内作为P-gp底物的潜力。通过检测P-gp ATPase活性来检测P-gp对四种非典型抗精神病药物和两种传统抗精神病药物以及已证实的底物维拉帕米的活性。用Michaelis-Menten方程对数据进行了拟合。V-max/K-m的排序为：维拉帕米(2.6)>；奎硫平(1.7)>；利培酮(1.4)>；奥氮平(0.8)>；氯丙嗪(0.7)>；氟哌啶醇(0.3)=氯氮平(0.3)。非典型抗精神病药物奎硫平和利培酮是相对较好的P-gp底物，尽管它们的亲和力没有维拉帕米那么高。奥氮平的亲和力中等，氯氮平的亲和力最低。这些结果表明，P-gp可能会不同程度地影响所有研究的非典型抗精神病药物的大脑通路。需要活体研究来证实这些发现。(C)2002 Elsevier Science Inc.保留所有权利。
The transmembrane transporter P-glycoprotein (P-gp) is an ATP-dependent efflux pump for a wide range of drugs. P-gp potentially limits access to brain tissue of psychoactive substrates, but little is known about its specificity for antipsychotics. The objective of this study was to assess the affinity of some atypical antipsychotic drugs in vitro for P-gp as indicative of their potential as P-gp substrates in vivo, The activity of P-gp towards four atypical and two conventional antipsychotics and a proven substrate, verapamil, was examined by their P-gp ATPase activity, a putative measure of P-gp affinity. The Michaelis-Menten equation was fitted to the data. The rank order of the ratio V-max/K-m was: verapamil (2.6) > quetiapine (1.7) > risperidone (1.4) > olanzapine (0.8) > chlorpromzaine (0.7) > haloperidol (0.3) = clozapine (0.3). The atypical antipsychotics quetiapine and risperidone were relatively good P-gp substrates, although their affinities were not as high as verapamil. Olanzapine showed intermediate affinity and clozapine showed the least affinity of the drugs studied. These results suggest that P-gp is likely to influence the access to the brain of all of the atypical antipsychotics studied to various degrees. In vivo studies are needed to confirm these findings. (C) 2002 Elsevier Science Inc. All rights reserved.