PGP Regulation of Antipsychotic Exposure and Effects

描述(由申请人提供)：拟议的由调查员发起的项目是对先前申请的修订，该申请得到了令人鼓舞的初步审查。其应用主要集中在P-糖蛋白(P-gp)作为大脑通路的重要调节因子以及抗精神病药物的药理作用方面。抗精神病药物是治疗伴有精神病性症状的严重精神疾病的主要药物干预手段。拟议的动物研究旨在产生可能有助于改善雪崩药物治疗结果的数据。虽然已经定义了消除apd的途径，但关于药物转运体在其处置和影响中的作用的数据很少。ABCB1(也称为mdr1)是ABC盒式转运蛋白家族中研究最广泛的基因，具有高度的多态特性，编码P-gp。P-gp通过将其底物排入肠腔、胆汁、尿液，并限制它们通过胎盘并在中枢神经系统中蓄积，从而对主要器官起到保护作用。我们将检验这一假设，即P-gp是大脑通路的重要调节器，并对非典型药物的一个亚类-进行药理作用。类似地，我们将测试在血脑屏障的内皮细胞中抑制和诱导P-gp是否分别增加或减少了大脑对apd的暴露和影响。其具体目的是：(1)利用转基因小鼠评价非典型的动作电位作为P-gp的底物；(2)确定P-gp抑制和诱导对血浆和组织中动作电位浓度的影响；(3)使用多巴胺的细胞外微透析来评估P-gp抑制动物脑内神经递质的变化；(4)测量伴随P-gp抑制的大鼠的行为变化，以预测抗精神病药物的疗效。这一新的数据可能会潜在地指导未来的人体试验，通过使用辅助的P-gp调节剂来改善apd的疗效和/或耐受性。这项研究的结果将为人类的翻译研究提供支持，以完善对严重精神疾病患者使用这类药物的治疗指南。

DESCRIPTION (provided by applicant): The proposed investigator-initiated project is a revision of a previous application that received an encouraging initial review. The application focuses on P-glycoprotein (P-gp) as an important modulator of brain access and, therefore, pharmacologic effects of antipsychotic drugs. Antipsychotic drugs (APD) are the primary pharmacological intervention in the treatment of severe mental illness with psychotic symptoms. The proposed animal studies are designed to produce data that may contribute to improving the outcome of pharmacotherapy with APD. While the pathways of elimination of the APD have been defined, only sparse data exist on the role of drug transporters in their disposition and effects. The most widely studied gene of the ABC cassette family of transporters, ABCB1 (also known as MDR1), is highly polymorphic and encodes for P-gp. P-gp plays a protective role for major organs by effluxing its substrates into the intestinal lumen, bile, urine, and by limiting their passage across the placenta and accumulation in the central nervous system. We will test the hypothesis that P-gp is an important modulator of brain access and pharmacologic effects of a subclass of APD, the atypicals. Similarly, we will test whether inhibition and induction of P-gp in the endothelial cells at the blood brain barrier increases or decreases, respectively, the brain exposure to, and effects of, APD. The specific aims are: (i) to evaluate the atypical APD as substrates of P-gp using transgenic mice; (ii) to determine the effects of P-gp inhibition and induction on plasma and tissue concentrations of APD; (iii) to assess neurotransmitter changes in the brain of P-gp inhibited animals using extracellular microdialysis of dopamine; and (iv) to measure behavioral changes in rats accompanying P-gp inhibition that are predictive of antipsychotic efficacy. This novel data may potentially guide future human trials to improve APD efficacy and/or tolerability with use of adjunctive P-gp modulators. The results of this research will provide support for translational studies in humans to refine treatment guidelines for the use of this class of medications in severely mentally ill patients.