Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA.
Invest Ophthalmol Vis Sci. 2011 Jul 23;52(8):5387-99. doi: 10.1167/iovs.10-6233.
To determine the influence of drug lipophilicity, ocular pigmentation, and species differences on transscleral solute transport.
The transport of eight β-blockers across excised sclera/sclera-choroid-RPE (SCRPE) of albino rabbit, pigmented rabbit, human, porcine, and bovine eyes was determined over 6 hours. The ex vivo transscleral β-blocker transport to the vitreous at the end of 6 hours was determined in euthanatized, pigmented Brown Norway rats. The thicknesses of the sclera and SCRPE and the melanin content in choroid-RPE (CRPE) were measured to determine whether species differences in drug transport can be explained on this basis.
Solute lipophilicity inversely correlated with the SCRPE cumulative percentage of transport in all species (R(2) ≥ 0.80). The CRPE impeded the SCRPE transport of all β-blockers (51%-64% resistance in the rabbits; 84%-99.8% in the bovine and porcine eyes) more than the sclera, with the impedance increasing with lipophilicity. SCRPE transport followed the trend albino rabbit > pigmented rabbit > human > porcine > bovine, and a cross-species comparison showed good Spearman's rho correlation (R(2) ≥ 0.85). Bovine (R(2) = 0.84), porcine (R(2) = 0.84), and human (R(2) = 0.71) SCRPE transport was more predictive than that in the rabbit models (R(2) = 0.60-0.61) of transscleral solute transport to the vitreous in rats. The CRPE concentrations were higher in pigmented rabbits than in albino rabbits. The melanin content of the CRPE exhibited the trend albino rabbit ≪ pigmented rabbit < porcine ∼ bovine < rat. Normalization to scleral thickness abolished the species differences in scleral transport. Normalization to SCRPE thickness and melanin content significantly reduced species differences in SCRPE transport.
Owing to the presence of pigment and drug binding, choroid-RPE is the principal barrier to transscleral β-blocker transport, with the barrier being more significant for lipophilic β-blockers. Although different in magnitude between species, sclera/SCRPE transport can be correlated between species. Tissue thickness accounts for the species differences in scleral transport. Differences in tissue thickness and melanin content largely account for the species differences in SCRPE transport.
确定药物脂溶性、眼内色素沉着和物种差异对巩膜外溶质转运的影响。
测定了 8 种β受体阻滞剂在白化兔、色素兔、人、猪和牛眼的巩膜/巩膜脉络膜-RPE（SCRPE）中的 6 小时内的转运情况。在处死的色素性褐挪威大鼠中，测定了 6 小时末玻璃体中β受体阻滞剂的体外经巩膜转运情况。测量巩膜和 SCRPE 的厚度以及脉络膜-RPE（CRPE）中的黑色素含量，以确定药物转运的物种差异是否可以基于此来解释。
在所有物种中，溶质脂溶性与 SCRPE 累积转运百分比呈负相关（R(2)≥0.80）。CRPE 对所有β受体阻滞剂的 SCRPE 转运都有阻碍作用（兔为 51%-64%；牛和猪眼为 84%-99.8%），比巩膜的阻碍作用更大，其阻碍作用随脂溶性的增加而增加。SCRPE 转运遵循白化兔>色素兔>人>猪>牛的趋势，跨物种比较显示出良好的斯皮尔曼 rho 相关性（R(2)≥0.85）。牛（R(2)=0.84）、猪（R(2)=0.84）和人（R(2)=0.71）的 SCRPE 转运比兔模型（R(2)=0.60-0.61）更能预测β受体阻滞剂在大鼠玻璃体中的经巩膜转运。色素兔的 CRPE 浓度高于白化兔。CRPE 中的黑色素含量呈白化兔≪色素兔<猪≈牛<大鼠的趋势。巩膜厚度归一化消除了巩膜转运的物种差异。SCRPE 厚度和黑色素含量的归一化显著降低了 SCRPE 转运的物种差异。
由于存在色素和药物结合，脉络膜-RPE 是巩膜β受体阻滞剂转运的主要屏障，亲脂性β受体阻滞剂的屏障作用更为显著。尽管在不同物种之间存在差异，但可以在物种之间对巩膜/SCRPE 转运进行相关。组织厚度解释了巩膜转运的物种差异。组织厚度和黑色素含量的差异在很大程度上解释了 SCRPE 转运的物种差异。
