PGP Regulation of Antipsychotic Exposure and Effects

描述（由申请人提供）：拟议的研究者发起的项目是对先前获得令人鼓舞的初步审查的申请的修订。应用的重点是p -糖蛋白（P-gp）作为一个重要的脑通路调节剂，因此，抗精神病药物的药理作用。抗精神病药物（APD）是治疗伴有精神病症状的严重精神疾病的主要药物干预。拟议的动物研究旨在产生可能有助于改善APD药物治疗结果的数据。虽然APD的消除途径已经确定，但只有稀疏的数据存在于药物转运体在其处置和效果中的作用。ABCB1（也称为MDR1）是ABC盒式转运蛋白家族中研究最广泛的基因，它是高度多态性的，编码P-gp。P-gp通过将其底物外排到肠腔、胆汁和尿液中，并通过限制其通过胎盘和在中枢神经系统的积累，对主要器官起保护作用。我们将验证P-gp是APD亚类（非典型性）脑通路和药理作用的重要调节剂的假设。同样，我们将测试血脑屏障内皮细胞中P-gp的抑制和诱导是否分别增加或减少脑暴露于APD和APD的影响。具体目的是：(i)利用转基因小鼠评价非典型APD作为P-gp的底物；（ii）确定P-gp抑制和诱导对血浆和组织中APD浓度的影响；（iii）利用细胞外微透析多巴胺评估P-gp抑制动物脑内神经递质变化；（iv）测量伴随P-gp抑制的大鼠的行为变化，预测抗精神病药物的疗效。这一新的数据可能会指导未来的人体试验，通过使用辅助P-gp调节剂来提高APD的疗效和/或耐受性。这项研究的结果将为人类的转化研究提供支持，以完善在严重精神疾病患者中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.