Kinetics of Drug Penetration Across the Cornea at a Microscopic Level

微观水平上药物穿过角膜的渗透动力学

• 批准号: 7681034
• 负责人: SANGLY P SRINIVAS
• 金额: $ 18.51万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7681034
• 关键词: Abbreviations; Chemicals; Computer Assisted; Confocal Microscopy; Cornea; Custom; Data; Development; Diffusion; Drug Administration Routes; Drug Design; Drug Kinetics; Drug Transport; Endothelium; Epithelial; Exhibits; Eye; Fluorescein; Fluoresceins; Fluorescence; Fluorescence Microscopy; Goals; Heterogeneity; In Vitro; Investigation; Lead; Measures; Microscopic; Microscopy; Modeling; Molecular Models; Molecular Structure; Molecular Weight; Oryctolagus cuniculus; Penetration; Pharmaceutical Preparations; Physiological; Principal Investigator; Scanning; Series; Skin; Spottings; Structure; Techniques; Thick; Time; Tissues; Topical application; Treatment Protocols; Validation; analog; anterior chamber; base; chemical property; design; dosage; in vivo; insight; instrument; ionization; knowledge base; lipophilicity; member; molecular modeling; monolayer; novel; pharmacokinetic model; programs; public health relevance; research study; stem; Abbreviations; Chemicals; Computer Assisted; Confocal Microscopy; Cornea; Custom; Data; Development; Diffusion; Drug Administration Routes; Drug Design; Drug Kinetics; Drug Transport; Endothelium; Epithelial; Exhibits; Eye; Fluorescein; Fluoresceins; Fluorescence; Fluorescence Microscopy; Goals; Heterogeneity; In Vitro; Investigation; Lead; Measures; Microscopic; Microscopy; Modeling; Molecular Models; Molecular Structure; Molecular Weight; Oryctolagus cuniculus; Penetration; Pharmaceutical Preparations; Physiological; Principal Investigator; Scanning; Series; Skin; Spottings; Structure; Techniques; Thick; Time; Tissues; Topical application; Treatment Protocols; Validation; analog; anterior chamber; base; chemical property; design; dosage; in vivo; insight; instrument; ionization; knowledge base; lipophilicity; member; molecular modeling; monolayer; novel; pharmacokinetic model; programs; public health relevance; research study; stem

DESCRIPTION (provided by applicant): Kinetics of Drug Penetration across the Cornea at a Microscopic Level Drugs applied topically to the eye access the intraocular tissues predominantly by penetration across the multi-layered cornea, consisting of a stratified epithelial layer, a thick collagenous stroma and a leaky monolayer of endothelium. Previous studies on topical drug kinetics to the eye have focused mainly on compartmental modeling of transport across the cornea. Such models have disregarded the inherent heterogeneity in the cornea, rendering them incapable of making sufficiently accurate predictions. The disregard for the heterogeneity in the cornea stems from the fact that experimental transcorneal concentration profiles of drugs are unavailable and difficult to obtain. Accordingly, only the average values of the drugs in the cornea, which are usually measured, have been employed in the development of pharmacokinetic modeling of topical drugs to the eye. This project will employ a novel custom-built confocal scanning microfluorometer to measure transcorneal profiles of a series of fluorescent compounds employed as drug analogs across rabbit cornea mounted in vitro. The resulting transcorneal concentration profiles will be employed to develop a phenomenologically-based non-compartmental pharmacokinetic model. The resulting model will then be employed to predict pharmacokinetics for topical administration of the fluorescent drug analogs. These predictions will be compared with in vivo data, which will be obtained for the same fluorescent compounds using another custom-built ocular spot-fluorometer. The latter instrument can measure average fluorescence from the cornea and anterior chamber. Overall, the results from this project involving in vivo and in vitro experiments is expected to yield detailed mechanistic understanding of topical drug kinetics and eventually enable rational drug design as well as the development of optimal drug dosage regimen. PUBLIC HEALTH RELEVANCE: More than 90% of the drugs to the eye are administered by topical administration. In this project, we propose to investigate how the topically administered drugs penetrate across the cornea into the eye. We expect to obtain a mechanistic understanding of the penetration, which is needed for rational drug design and optimal design of dosage regimen.

描述（由申请人提供）：在微观水平的药物下，药物渗透的动力学局部用于眼睛，该药物局部应用于眼内组织，主要是通过跨越多层角膜的渗透，由分层的上皮层，由厚胶原瘤和内皮层的漏水单层组成。先前关于局部药物动力学的研究主要集中在跨角膜的转运室建模上。这样的模型无视角膜中固有的异质性，使它们无法进行足够准确的预测。无视角膜中异质性的原因是，药物的实验性跨侧浓度剖面是不可用的，难以获得。因此，通常测量角膜中药物的平均值已用于开发局部药物的药代动力学建模。该项目将采用一种新型的定制共聚焦扫描微荧光仪，以测量一系列在体外安装的兔角膜上用作型药物类似物的荧光化合物的跨侧剖面。最终的跨侧浓度谱将用于开发基于现象学的非室内药代动力学模型。然后，将采用所得模型来预测荧光药物类似物局部给药的药代动力学。这些预测将与体内数据进行比较，该数据将使用另一种定制的眼点荧光仪对相同的荧光化合物获得。后一种仪器可以测量角膜和前腔的平均荧光。总体而言，该项目涉及体内和体外实验的结果有望对局部药物动力学产生详细的机械理解，并最终使理性药物设计以及最佳药物剂量方案的开发。公共卫生相关性：局部管理部门管理超过90％的药物。在这个项目中，我们建议研究局部施用的药物如何穿透角膜进入眼睛。我们希望获得对渗透率的机械理解，这是理性药物设计和剂量方案最佳设计所需的。