Assessment of subconjunctival delivery with model ionic permeants and magnetic resonance imaging
Assessment of subconjunctival delivery with model ionic permeants and magnetic resonance imaging
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DOI：
10.1007/s11095-004-7669-3
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发表时间：
2004-12-01
影响因子：
3.7
通讯作者：
Jeong, EK
中科院分区：
文献类型：
--
作者：
Li, SK;Molokhia, SA;Jeong, EK
目的.目的是通过核磁共振成像（MRI）评估结膜下注射模型离子渗透剂后的渗透和清除。新西兰白色兔为动物模型，锰离子（Mn 2+）和乙二胺四乙酸锰络合物（MnEDTA（2-））为模型渗透物。本研究分为三个部分：体外、死后和体内。采用离体巩膜在体外并排扩散池中进行经巩膜被动渗透实验。结膜下给药实验在家兔死后和体内进行。通过MRI测定结膜下注射后探针渗透物在结膜下空间的分布和消除。离体巩膜的数据表明，大的有效孔径的跨巩膜运输和可忽略不计的孔电荷的离子渗透剂的渗透后的影响。Mn ~（2+）和MnEDTA ~（2-）在离体巩膜中的渗透系数分别为3.6 × 10 ~（-5）cm/s和2.4 × 10 ~（-5）cm/s。尽管在体外观察到相对高的巩膜渗透性，但体内结膜下注射没有提供Mn 2+和MnEDTA（2-）到地球仪中的显著渗透;眼睛中的渗透物浓度低于检测限，其对应于小于注射溶液浓度的0.05%（例如，当使用40 mM注射溶液时小于0.02mM）。注射后，观察到结膜下囊的体积和囊中渗透物的浓度随时间降低，这可能导致体内结膜下吸收低于预期。与体内实验结果不同，家兔死后实验显示Mn 2+和MnEDTA（2-）明显渗透到地球仪中，渗透物主要进入眼前段。这种差异表明血管系统清除是被动经巩膜转运的主要屏障。数据还显示，睫状体褶皱部/睫状体平坦部是极性渗透物的被动经巩膜药物递送的阻力最小的途径，并且有迹象表明在眼睛后部存在另一个屏障，可能是视网膜上皮和/或布鲁赫膜。离子渗透剂在体内的结膜下递送不能通过体外结果定量预测。MRI是传统药代动力学方法的非侵入性补充技术。它可以提供对眼部药代动力学的深入了解，而不会在传统药代动力学研究中，当缺乏血管屏障时，在手术过程中可能发生的渗透物再分布。
Purpose. The objective was to assess the permeation and clearance of model ionic permeants after subconjunctival injection with nuclear magnetic resonance imaging (MRI).Methods. New Zealand white rabbit was the animal model and manganese ion (Mn2+) and manganese ethylenediaminetetraacetic acid complex (MnEDTA(2-)) were the model permeants. The current study was divided into three parts: in vitro, postmortem, and in vivo. Transscleral passive permeation experiments were conducted with excised sclera in side-by-side diffusion cells in vitro. Subconjunctival delivery experiments were conducted with rabbits postmortem and in vivo. The distribution and elimination of the probe permeants from the subconjunctival space after subconjunctival injections were determined by MRI.Results. The data of excised sclera in vitro suggest large effective pore size for transscleral transport and negligible pore charge effects upon the permeation of the ionic permeants. The permeability coefficients of Mn2+ and MnEDTA(2-) across the sclera in vitro were 3.6 x 10(-5) cm/s and 2.4 x 10(-5) cm/s, respectively. Although relatively high sclera permeability was observed in vitro, subconjunctival injections in vivo did not provide significant penetration of Mn2+ and MnEDTA(2-) into the globe; permeant concentrations in the eye were below the detection limit, which corresponds to less than 0.05% of the concentration of the injection solution (e.g., less than 0.02 mM when 40 mM injection solution was used). The volume of the subconjunctival pocket and the concentration of the permeants in the pocket were observed to decrease with time after the injection, and this could contribute to the lower than expected subconjunctival absorption in vivo. Different from the results in vivo, experiments with rabbits postmortem show significant penetration of Mn2+ and MnEDTA(2-) into the globe with the permeants primarily delivered into the anterior segment of the eye. This difference suggests blood vasculature clearance as a main barrier for passive transscleral transport. The data also show that the pars plicata/pars plana is the least resistance pathway for passive transscleral drug delivery of the polar permeants, and there are indications of the presence of another barrier, possibly the retinal epithelium and/or Bruch's membrane, at the back of the eye.Conclusions. Subconjunctival delivery of the ionic permeants in vivo cannot be quantitatively predicted by the in vitro results. MRI is a noninvasive complementary technique to traditional pharmacokinetic methods. It can provide insights into ocular pharmacokinetics without permeant redistribution that can occur in surgical procedure postmortem in traditional pharmacokinetic studies when the blood vasculature barrier is absent.