PGP Regulation of Antipsychotic Exposure and Effects

PGP 抗精神病药物暴露和作用的调节

基本信息

批准号：
7410184
负责人：
C Lindsay LINDSAY DEVANE
金额：
$ 24.92万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-14 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7410184
关键词：
ABCB1 gene Acute Animal Behavior Animal Experiments Animals Antipsychotic Agents Area Bile fluid Blood - brain barrier anatomy Brain Class Clozapine Control Animal Control Groups Data Dopamine Dose Drug Delivery Systems Drug Kinetics Drug or chemical Tissue Distribution Endothelial Cells Exposure to Family Future Genes Goals Guidelines HIV Infections Human Injection of therapeutic agent Intervention Intestines Measures Medial Mentally Ill Persons Microdialysis Motor Mus Neuraxis Neurotransmitters Organ Outcome P-Glycoprotein P-Glycoproteins Pathway interactions Patients Peripheral Pharmaceutical Preparations Pharmacodynamics Pharmacotherapy Placenta Plasma Play Prefrontal Cortex Psychiatry Range Rattus Regulation Research Research Design Research Personnel Risperidone Role Sampling Site Surrogate Markers Symptoms Testing Tissues Transgenic Mice Transgenic Organisms Urine aripiprazole atypical antipsychotic behavior measurement clinical efficacy drug distribution drug efficacy extracellular improved in vivo inhibitor/antagonist innovation intraperitoneal neurotransmitter release novel novel therapeutics olanzapine oncology programs putamen quetiapine research study response severe mental illness translational study uptake ziprasidone

项目摘要

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.

描述（由申请人提供）：拟议的调查员发起的项目是对先前申请的修订，该申请获得了令人鼓舞的初步审查。该应用的重点是P-糖蛋白（P-GP）作为大脑进入的重要调节剂，因此是抗精神病药的药理作用。抗精神病药（APD）是治疗患有精神病症状的严重精神疾病的主要药理干预措施。拟议的动物研究旨在产生可能有助于改善APD药物疗法结果的数据。尽管已经定义了消除APD的途径，但仅在药物转运蛋白在其处置和效果中的作用上存在稀疏数据。 ABC盒转运蛋白的ABCB1（也称为MDR1）的最广泛研究的基因是高度多态性的，并且编码了P-gp。 P-gp通过将其底物排出肠腔，胆汁，尿液，并限制其通过胎盘穿过胎盘并在中枢神经系统中积累来对主要器官发挥保护作用。我们将检验以下假设：P-gp是APD亚型，非典型人群的大脑通道和药理作用的重要调节剂。同样，我们将测试在血脑屏障处的内皮细胞中P-gp的抑制和诱导是否会分别增加或减少，大脑暴露于APD的大脑和影响。具体目的是：（i）使用转基因小鼠评估非典型APD作为P-gp的底物；（ii）确定P-gp抑制和诱导对APD血浆和组织浓度的影响；（iii）使用多巴胺的细胞外微透析抑制P-gp抑制动物的神经递质的变化；（iv）测量伴随P-gp抑制的大鼠的行为变化，这些抑制作用可预测抗精神病药的功效。该新型数据可能有可能指导未来的人类试验，以通过使用辅助P-gp调节剂来提高APD功效和/或耐受性。这项研究的结果将为人类翻译研究提供支持，以完善治疗指南，以在严重患者患者中使用此类药物。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Antipsychotic drugs inhibit the function of breast cancer resistance protein.

抗精神病药物会抑制乳腺癌耐药蛋白的功能。

DOI：
10.1111/j.1742-7843.2008.00298.x
发表时间：
2008
期刊：
Basic & clinical pharmacology & toxicology
影响因子：
3.1
作者：
Wang,Jun-Sheng;Zhu,Hao-Jie;Markowitz,JohnS;Donovan,JenniferL;Yuan,Hong-Jie;Devane,CLindsay
通讯作者：
Devane,CLindsay

Evaluation of antipsychotic drugs as inhibitors of multidrug resistance transporter P-glycoprotein.

抗精神病药物作为多药耐药转运蛋白 P-糖蛋白抑制剂的评价。

DOI：
10.1007/s00213-006-0437-9
发表时间：
2006
期刊：
Psychopharmacology
影响因子：
3.4
作者：
Wang,Jun-Sheng;Zhu,Hao-Jie;Markowitz,JohnS;Donovan,JenniferL;DeVane,CLindsay
通讯作者：
DeVane,CLindsay