Department of Chemical Engineering, University of Florida, Gainesville, Florida, USA.
Pharm Res. 2010 Apr;27(4):699-711. doi: 10.1007/s11095-010-0066-1. Epub 2010 Feb 25.
To develop a kinetic model for representing the diffusion and partitioning of Rhodamine B (RhB), a fluorescent lipophilic molecule, across the cornea for gaining insights into pharmacokinetics of topical drugs to the eye.
Rabbit corneas mounted underneath a custom-built scanning microfluorometer were perfused with Ringers on both sides of the tissue. After a step change in RhB on the tear side, transients of trans-corneal fluorescence of RhB were measured at a depth resolution approximately 8 microm.
RhB distribution exhibited discontinuities at the interface between epithelium and stroma, and between stroma and endothelium. In each of the layers, fluorescence was non-uniform. Fluorescence was elevated in the epithelium and endothelium relative to the stroma. Modeling of RhB transport by diffusion in each layer and stipulation of partitioning of RhB at the cellular interfaces were required to account for trans-corneal penetration kinetics of RhB. The model parameters, estimated using the unsteady state trans-corneal RhB profiles, were found to be sensitive, and the model predicted the experimental profiles accurately.
Conventional pharmacokinetic models that depict cornea as a single compartment do not predict the depth-dependent kinetics of RhB penetration. The proposed model incorporates realistic transport mechanisms and thereby highlights the influence of physicochemical properties of drugs on trans-corneal kinetics.
建立一个动力学模型，以描述荧光亲脂性分子罗丹明 B（RhB）在角膜中的扩散和分配，从而深入了解眼部局部药物的药代动力学。
将兔角膜置于定制的扫描微荧光计下方，组织两侧均用林格氏液灌流。在泪液侧 RhB 发生阶跃变化后，以约 8 微米的深度分辨率测量 RhB 的跨角膜荧光瞬变。
RhB 分布在上皮和基质之间以及基质和内皮之间的界面处存在不连续性。在每个层中，荧光不均匀。上皮和内皮中的荧光相对于基质升高。为了解释 RhB 的跨角膜渗透动力学，需要在每个层中通过扩散对 RhB 进行建模，并规定 RhB 在细胞界面处的分配。使用非稳态跨角膜 RhB 分布来估计模型参数，发现这些参数具有敏感性，并且模型可以准确预测实验分布。
传统的药代动力学模型将角膜描绘为一个单一隔室，无法预测 RhB 渗透的深度依赖性动力学。所提出的模型结合了现实的传输机制，从而突出了药物的物理化学性质对跨角膜动力学的影响。
