Department of Ophthalmology, Jacobs Retina Center at Shiley Eye Center, University of California-San Diego, 9415 Campus Point Drive, La Jolla, CA 92093-0946, USA.
J Ocul Pharmacol Ther. 2011 Apr;27(2):157-62. doi: 10.1089/jop.2010.0155. Epub 2011 Feb 25.
To evaluate the intraocular pharmacokinetics of octadecyloxyethyl-cyclic-cidofovir (ODE-cCDV) after intravitreal injection into rabbit eyes.
Twenty-seven New Zealand red rabbits (27 eyes) received intravitreal injections of (14)C-labeled ODE-cCDV (100 μg drug suspended in 5% dextrose), and ocular tissues were collected from 3 rabbits at each predetermined time point (1 h, 1 day, 3 days, 1 week, 2 weeks, 3 weeks, 5 weeks, and 9 weeks) after the injection. The eye globes were enucleated, and the vitreous, retina, and choroids were separated and harvested into pre-weighed scintillation vials. Levels of ODE-cCDV were measured by counting in a liquid scintillation counter, and pharmacokinetic (PK) parameters were determined. In addition, 3 eyes of 3 animals were used for autoradiography study at day 1, week 3, and week 6.
ODE-cCDV in vitreous as a whole followed a 2-phase first-order elimination, whereas ODE-cCDV in retina and choroid manifested a nearly steady state during the first 3 weeks and then followed a first-order elimination with the apparent elimination half-life of 10.1 and 7.2 days. For vitreous, apparent elimination half-life was 25 days. However, the drug mean residence time was much longer in retina (17.6 days) and choroid (19.6 days) than that in the vitreous (11.6 days). The drug exposure to the retina [area under the curve (AUC) = 1120837.1 ng · day/mL] was greater than the exposure to the vitreous (AUC = 958645.8 ng · day/mL) and the choroid (AUC = 415407.47).
A crystalline lipid prodrug, ODE-cCDV, has longer vitreous half-life than that in other ocular tissues due to its solid drug depot formation in vitreous. Over time, dissolved free ODE-cCDV from drug depot feeds and accumulates in the retina.
评估十八烷氧基乙基环膦酸酯-cidofovir（ODE-cCDV）经玻璃体内注射入兔眼后的眼内药代动力学。
27 只新西兰白兔（27 只眼）接受（14）C 标记的 ODE-cCDV（100μg 药物悬浮于 5%葡萄糖中）玻璃体内注射，注射后 1 小时、1 天、3 天、1 周、2 周、3 周、5 周和 9 周的每个预定时间点，从 3 只兔子的眼睛中收集眼组织。眼球被剜出，将玻璃体、视网膜和脉络膜分离并收获到预先称重的闪烁瓶中。通过液体闪烁计数器计数来测量 ODE-cCDV 的水平，并确定药代动力学（PK）参数。此外，在第 1 天、第 3 周和第 6 周，使用 3 只动物的 3 只眼进行放射自显影研究。
玻璃体中的 ODE-cCDV 整体遵循两相一阶消除，而视网膜和脉络膜中的 ODE-cCDV 在最初的 3 周内呈现近乎稳定的状态，然后遵循一阶消除，表观消除半衰期为 10.1 和 7.2 天。玻璃体中的表观消除半衰期为 25 天。然而，药物在视网膜（17.6 天）和脉络膜（19.6 天）中的平均停留时间比玻璃体（11.6 天）长得多。药物对视网膜的暴露量[曲线下面积（AUC）=1120837.1ng·天/mL]大于对玻璃体（AUC=958645.8ng·天/mL）和脉络膜（AUC=415407.47ng·天/mL）的暴露量。
结晶脂质前药 ODE-cCDV 由于在玻璃体中形成固体药物储库，其玻璃体半衰期长于其他眼组织。随着时间的推移，来自药物储库的溶解游离 ODE-cCDV 会在视网膜中积累。
