School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Invest Ophthalmol Vis Sci. 2024 Oct 1;65(12):14. doi: 10.1167/iovs.65.12.14.
The purpose of this work was to understand the impact of melanin binding on ocular pharmacokinetics after administration of a high-binder model drug via different administration routes.
We applied levofloxacin to pigmented and albino rabbits as eye drops (single and multiple), as well as by intravitreal and intravenous injections. Ocular tissues and plasma were analyzed for levofloxacin concentrations with liquid chromatography-mass spectrometry (LC-MS/MS), and pharmacokinetic parameters were calculated.
The data show enrichment of levofloxacin and weeks-long retention in pigmented tissues. Upon intravitreal injection, the area under the curve (AUC) values in pigmented tissues were about 9 to 15 times higher than the respective values in the albino rabbits, but this difference expanded to 255- to 951-fold following topical eye drop administration. Multiple dosing of eye drops led to substantial accumulation of levofloxacin in the pigmented tissues: AUC values were 3 to 12 times higher than after intravitreal injection. The AUCs were much lower after single topical or intravenous drug administrations. High drug levels (0.1-35 µM) were always observed in the neural retinas of pigmented eyes; the highest exposure was seen after intravitreal administration followed by multiple doses of topical drops. Single topical instillation and intravenous injections to the albino rabbits resulted in vitreal bioavailability values of 0.009% and 0.003%, respectively.
Melanin binding can be used to achieve targeted drug delivery and extended retention in pigmented ocular tissues. The results from topical multiple dosing experiments suggest that eye drop treatment may yield drug exposures and responses comparable to intravitreal delivery, even in the retinal pigment epithelium and choroid.
本研究旨在了解高结合模型药物经不同给药途径给药后，黑色素结合对眼部药代动力学的影响。
我们将左氧氟沙星应用于有色和白化兔的眼部滴注（单次和多次），以及玻璃体内和静脉内注射。采用液相色谱-质谱联用（LC-MS/MS）法分析眼部组织和血浆中的左氧氟沙星浓度，并计算药代动力学参数。
数据显示，左氧氟沙星在有色组织中发生蓄积，并可保持数周。玻璃体内注射时，有色组织中的曲线下面积（AUC）值约为白化兔的 9 至 15 倍，但局部滴眼后，这一差异扩大至 255 至 951 倍。多次滴眼导致左氧氟沙星在有色组织中大量蓄积：AUC 值比玻璃体内注射高 3 至 12 倍。单次局部或静脉内给药后 AUC 值要低得多。有色眼睛的神经视网膜中始终观察到较高的药物水平（0.1-35µM）；玻璃体内注射后，多次局部滴注的暴露量最高。单次局部滴注和静脉注射给白化兔，玻璃体内生物利用度分别为 0.009%和 0.003%。
黑色素结合可用于实现靶向药物递送和延长在有色眼部组织中的保留时间。多次局部滴眼实验的结果表明，滴眼治疗可能产生与玻璃体内给药相当的药物暴露和反应，即使在视网膜色素上皮和脉络膜也是如此。
