School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1, 70210, Kuopio, Finland.
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1, 70210, Kuopio, Finland.
Exp Eye Res. 2023 Oct;235:109638. doi: 10.1016/j.exer.2023.109638. Epub 2023 Aug 30.
Although mouse models are widely used in retinal drug development, pharmacokinetics in mouse eye is poorly understood. In this study, we applied non-invasive in vivo fluorophotometry to study pharmacokinetics of intravitreal fluorescein sodium (molecular weight 0.38 kDa) and fluorescein isothiocyanate-dextran (FD-150; molecular weight 150 kDa) in mice. Intravitreal half-lives of fluorescein and FD-150 in mouse eyes were 0.53 ± 0.06 h and 2.61 ± 0.86 h, respectively. These values are 8-230 times shorter than the elimination half-lives of similar compounds in the human vitreous. The apparent volumes of distribution in the mouse vitreous were close to the anatomical volume of the mouse vitreous (FD-150, 5.1 μl; fluorescein, 9.6 μl). Dose scaling factors were calculated from mouse to rat, rabbit, monkey and human translation. Based on pharmacokinetic modelling and compound concentrations in the vitreous and anterior chamber, fluorescein is mainly eliminated posteriorly across blood-retina barrier, but FD-150 is cleared via aqueous humour outflow. The results of this study improve the knowledge of intravitreal pharmacokinetics in mouse and facilitate inter-species scaling in ocular drug development.
尽管小鼠模型在视网膜药物开发中被广泛应用，但对其眼部的药代动力学仍知之甚少。在这项研究中，我们应用非侵入性活体荧光光度法研究了玻璃体内荧光素钠（分子量 0.38 kDa）和异硫氰酸荧光素-葡聚糖（FD-150；分子量 150 kDa）在小鼠眼中的药代动力学。小鼠眼中荧光素和 FD-150 的半衰期分别为 0.53 ± 0.06 h 和 2.61 ± 0.86 h，分别为人类玻璃体中类似化合物消除半衰期的 8-230 倍。玻璃体内的表观分布容积接近小鼠玻璃体的解剖学容积（FD-150，5.1 μl；荧光素，9.6 μl）。根据从鼠到大鼠、兔、猴和人的翻译计算了剂量换算因子。基于药代动力学模型和玻璃体内及前房内的化合物浓度，荧光素主要通过血视网膜屏障向后消除，但 FD-150 通过房水流出清除。本研究结果提高了对小鼠玻璃体内药代动力学的认识，并促进了眼内药物开发中的种间缩放。
