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Localized modulation of RPE P-gp/MRP activity for back-of-the-eye drug delivery

局部调节 RPE P-gp/MRP 活性以实现眼后药物输送

基本信息

批准号：
7489880
负责人：
Soumyajit Majumdar
金额：
$ 10.39万
依托单位：
UNIVERSITY OF MISSISSIPPI
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7489880
关键词：
Affect Alveolar Anti-Bacterial Agents Anti-Inflammatory Agents Anti-inflammatory Antiviral Agents Back Blood Circulation Brain Cells Choroid Cornea Diabetic Retinopathy Diffusion Disease Dose Drug Delivery Systems Drug Interactions Drug Kinetics Endophthalmitis Erythromycin Eye Eye diseases Eyedrops Frequencies Generations Glycine decarboxylase Half-Life Intestines Kidney Lateral Lead Localized Macular degeneration Maintenance Mediating Microdialysis Modeling Neural Retina Numbers Oryctolagus cuniculus P-Glycoprotein P-Glycoproteins Penetration Pharmaceutical Preparations Property Proteins Quinidine Research Personnel Research Project Grants Retinal Retinal Detachment Retinoblastoma Risk Route Sampling Sclera Structure of retinal pigment epithelium Study Section Techniques Therapeutic Tissues Topical agent Topical application Treatment outcome Vitreous humor Xenobiotics antitumor agent base basolateral membrane compliance behavior conjunctiva improved inhibitor/antagonist novel novel strategies posterior eyeball chamber prednisolone secondary infection tumor

项目摘要

DESCRIPTION (provided by applicant): Efflux mediated by P-glycoprotein (P-gp) and multidrug resistance protein (MRP) expressed on the basolateral membrane of the RPE makes drug delivery to the posterior ocular chamber a challenging task. Currently, direct intravitreal administration is the most effective mode of drug delivery for back-of-the-eye diseases. This route of administration, however, is associated with a number of risks such as retinal detachment, secondary infections etc. The objective of this proposal is to elucidate whether topically applied (as eye drops) P-gp and/or MRP substrates and/or inhibitors can modulate the activity of the efflux proteins, P- gp and/or MRP, expressed on the retinal pigmented epithelium (RPE), and thus alter ocular pharmacokinetics of systemically/intravitreally co-administered substrates. This application is based on the hypothesis that topically applied P-gp/MRP substrates can interact with P-gp/MRP expressed on the basolateral membrane of the RPE and modulate their efflux activity. P-gp/MRP substrates, following topical instillation, may reach the sclera either by lateral diffusion along the corneal-scleral junction, or by permeating across the conjunctiva into the sclera. The sclera and the underlying choroid do not pose a significant barrier to drug diffusion. Thus, a fraction of the topically applied agent can penetrate to the RPE and potentially interact with and influence the efflux activity of P-gp/MRP expressed on the basolateral membrane of the RPE. Topically applied P-gp/MRP substrates could thus affect RPE's barrier properties with respect to P-gp/MRP substrates. Consequently, drug penetration into the back-of-the-eye from the systemic circulation could be significantly enhanced. Conversely, topically applied P-gp/MRP substrates may decrease elimination of intravitreally administered substrates, and could thus prolong their retention in the back-of-the eye ocular tissues. Preliminary studies indicate that the vitreal elimination half-life of intravitreally administered quinidine is increased almost 2.5-folds in the presence of topically co-administered erythromycin. The novel studies proposed in this application will delineate the effect of topically applied P-gp/MRP substrates on ocular pharmacokinetics of systemically or intravitreally administered substrates in an anesthetized rabbit model. Quinidine, a substrate of P-gp/MRP, and, whose interaction with RPE P-gp has been demonstrated, will be employed as a marker compound in these exploratory studies. Erythromycin and prednisolone, commonly employed topical agents and established substrates of P-gp and/or MRP, will be administered topically. Thus, this application seeks to evaluate the effect of topically administered erythromycin and prednisolone (3 doses each) on ocular pharmacokinetics of (a) intravitreally and (b) systemically administered quinidine. It is expected that based on the findings from this study a novel approach for localized modulation of the efflux activities of RPE's P-gp and/or MRP can be developed and utilized for back-of-the-eye drug delivery. /Relevance Efflux mediated by P-glycoprotein (P-gp) and multidrug resistance proteins (MRP) expressed on the retinal pigmented epithelium makes drug delivery to the posterior chamber ocular tissues, or back-of-the-eye, a challenging task. Currently, direct intravitreal administration is the preferred mode of drug delivery for back-of- the-eye diseases. This route of administration, however, is associated with a number of risks. The studies proposed in this application will explore a noninvasive strategy for localized inhibition of the efflux activities of P-gp and MRP, which could lead to the generation or maintenance of enhanced drug concentrations in back- of-the-eye ocular tissues, following systemic or intravitreal administration. Results from this research project may thus improve treatment outcomes for posterior chamber ocular diseases such as endophthalmitis, diabetic retinopathy, macular degeneration, retinoblastoma and other intraocular tumors.

描述（由申请人提供）：RPE基底外侧膜上表达的p -糖蛋白（P-gp）和多药耐药蛋白（MRP）介导的外排使得药物递送到眼后腔成为一项具有挑战性的任务。目前，直接玻璃体内给药是治疗眼后疾病最有效的给药方式。然而，这种给药途径与许多风险相关，如视网膜脱离、继发感染等。本建议的目的是阐明局部应用（如滴眼液）P-gp和/或MRP底物和/或抑制剂是否可以调节在视网膜色素上皮（RPE）上表达的外排蛋白P-gp和/或MRP的活性，从而改变系统/玻璃体内共给药底物的眼药代动力学。这一应用是基于一个假设，即局部应用的P-gp/MRP底物可以与RPE基底侧膜上表达的P-gp/MRP相互作用，并调节其外排活性。P-gp/MRP底物在局部滴入后，可能通过沿角膜-巩膜交界处的外侧扩散或通过结膜渗透进入巩膜到达巩膜。巩膜和下面的脉络膜对药物扩散没有明显的障碍。因此，局部涂抹剂的一小部分可以渗透到RPE中，并可能与RPE基底侧膜上表达的P-gp/MRP相互作用并影响其外排活性。因此，局部应用P-gp/MRP底物会影响RPE相对于P-gp/MRP底物的屏障性能。因此，药物从体循环进入眼后的渗透可以显著增强。相反，局部应用P-gp/MRP底物可能会减少玻璃体内给药底物的消除，从而延长其在眼后眼组织中的保留时间。初步研究表明，在局部联合给药红霉素的情况下，玻璃体内给药奎尼丁的玻璃体消除半衰期增加了近2.5倍。本应用程序提出的新研究将描述局部应用P-gp/MRP底物对全身或玻璃体内给药底物在麻醉兔模型中的眼药代动力学的影响。奎尼丁是P-gp/MRP的底物，与RPE P-gp的相互作用已被证实，将在这些探索性研究中作为标记化合物。红霉素和强的松龙是常用的外用药物和P-gp和/或MRP的既定底物，将局部给药。因此，本申请旨在评估局部给药红霉素和强的松龙（各3剂）对(a)玻璃体内给药和(b)全身给药奎尼丁的眼药代动力学的影响。基于本研究的结果，可以开发一种局部调节RPE的P-gp和/或MRP外排活动的新方法，并将其用于眼后给药。视网膜色素上皮上表达的p -糖蛋白（P-gp）和多药耐药蛋白（MRP）介导的外排使得药物递送到后房眼组织或眼后成为一项具有挑战性的任务。目前，直接玻璃体内给药是治疗眼后疾病的首选给药方式。然而，这种给药方式伴随着许多风险。本申请中提出的研究将探索一种非侵入性策略来局部抑制P-gp和MRP的外排活性，这可能导致在全身或玻璃体内给药后眼后组织中产生或维持增强的药物浓度。因此，本研究项目的结果可能会改善眼内炎、糖尿病视网膜病变、黄斑变性、视网膜母细胞瘤和其他眼内肿瘤等后房眼病的治疗效果。