Kinetics of Drug Penetration Across the Cornea at a Microscopic Level

描述（由申请人提供）：显微水平下药物穿过角膜的动力学局部应用于眼睛的药物主要通过穿过多层角膜进入眼内组织，多层角膜由分层上皮层、厚胶原基质和渗漏的单层内皮组成。以前对局部药物动力学的研究主要集中在跨角膜运输的室室模型上。这些模型忽略了角膜的内在异质性，使得它们无法做出足够准确的预测。对角膜异质性的忽视源于这样一个事实，即药物经角膜的实验浓度谱是不可用的，而且很难获得。因此，在开发局部药物对眼睛的药代动力学模型时，仅采用通常测量的角膜中药物的平均值。本项目将采用一种新型的定制共聚焦扫描微荧光仪来测量一系列用作药物类似物的荧光化合物在体外安装的兔角膜上的经角膜分布。由此产生的经角膜浓度分布将被用于开发基于现象学的非室室药代动力学模型。由此产生的模型将被用来预测局部给药荧光药物类似物的药代动力学。这些预测将与体内数据进行比较，这些数据将使用另一种定制的眼点荧光仪获得相同荧光化合物的体内数据。后一种仪器可以测量角膜和前房的平均荧光。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制理解，并最终实现合理的药物设计以及最佳药物给药方案的开发。公共卫生相关性：超过90%的眼部用药是局部给药。在这个项目中，我们建议研究局部给药如何穿过角膜进入眼睛。我们希望通过对渗透机理的了解，为药物的合理设计和给药方案的优化设计提供依据。

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.