Ocular Tissue Distribution of Omidenepag Isopropyl in Rabbits and Cynomolgus Monkeys.

IF 2.6 3区医学 Q2 OPHTHALMOLOGY Translational Vision Science & Technology Pub Date : 2024-11-04 DOI:10.1167/tvst.13.11.6

Kenzo Yamamura, Hidetoshi Mano, Masahiro Fuwa, Ryo Iwamura, Noriko Odani-Kawabata

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Abstract

Purpose: To evaluate the ocular distribution of omidenepag isopropyl (OMDI) and its active form omidenepag (OMD), an EP2 receptor agonist, after topical administration of OMDI into rabbit and monkey eyes, and to determine whether OMDI and OMD interact with target receptors or enzymes of other antiglaucoma agents.

Methods: Both eyes of six rabbits and of 14 monkeys were topically instilled with 0.03% [14C]-OMDI. Rabbits were sacrificed after one to four hours, and ocular tissues were collected. Monkeys were sacrificed after 0.25 to 24 hours, and blood and ocular tissues were collected. Radioactivity was measured in each sample. The interactions of OMDI and OMD with the receptors and enzymes associated with the mechanisms of action of other antiglaucoma agents were evaluated.

Results: Most radioactivity applied to rabbit eyes was recovered as OMD from the cornea, aqueous humor, and iris-ciliary body. Similarly, high concentrations of radioactivity were observed in monkey cornea, bulbar/palpebral conjunctiva, and trabecular meshwork. OMD bound to EP2 receptors, but neither OMD nor OMDI bound to α2A, β1, and β2 adrenergic receptors or inhibited enzymatic activities of CA1 and CA2. OMD and OMDI had little or no effect on ROCK1 and ROCK2.

Conclusions: OMDI rapidly permeates rabbit and monkey corneas and is converted to OMD, which distributes into anterior ocular tissues. Neither OMD nor OMDI interacted with the target receptors or enzymes of other antiglaucoma agents, suggesting that OMD interacts highly selectively with EP2 receptors.

Translational relevance: OMDI is a specific antiglaucoma agent that interacts selectively with ocular EP2 receptors.

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奥米替尼帕格异丙酯在家兔和猴眼部组织中的分布。

目的：评估兔眼和猴眼局部注射奥米地帕异丙酯（OMDI）及其活性形式奥米地帕（OMD）（一种 EP2 受体激动剂）后的眼部分布情况，并确定 OMDI 和 OMD 是否与其他抗青光眼药物的靶受体或酶发生相互作用：方法：向 6 只兔子和 14 只猴子的双眼局部注射 0.03% [14C]-OMDI 。一至四小时后兔子被处死，收集眼组织。猴子在 0.25 至 24 小时后被处死，收集血液和眼组织。测量每个样本的放射性。评估了 OMDI 和 OMD 与其他抗青光眼药物作用机制相关的受体和酶的相互作用：应用于兔眼的大部分放射性物质都以 OMD 的形式从角膜、房水和虹膜睫状体中回收。同样，在猴子的角膜、球结膜/睑结膜和小梁网也观察到了高浓度的放射性。OMD 能与 EP2 受体结合，但 OMD 和 OMDI 都不能与 α2A、β1 和 β2 肾上腺素能受体结合，也不能抑制 CA1 和 CA2 的酶活性。OMD 和 OMDI 对 ROCK1 和 ROCK2 几乎没有影响：结论：OMDI 可快速渗透兔和猴的角膜，并转化为 OMD，分布到眼前组织。OMD和OMDI均未与其他抗青光眼药物的靶受体或酶发生相互作用，这表明OMD与EP2受体的相互作用具有高度选择性：OMDI是一种特异性抗青光眼药物，可选择性地与眼部EP2受体相互作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Translational Vision Science & Technology Engineering-Biomedical Engineering

CiteScore

5.70

自引率

3.30%

发文量

346

审稿时长

25 weeks

期刊介绍： Translational Vision Science & Technology (TVST), an official journal of the Association for Research in Vision and Ophthalmology (ARVO), an international organization whose purpose is to advance research worldwide into understanding the visual system and preventing, treating and curing its disorders, is an online, open access, peer-reviewed journal emphasizing multidisciplinary research that bridges the gap between basic research and clinical care. A highly qualified and diverse group of Associate Editors and Editorial Board Members is led by Editor-in-Chief Marco Zarbin, MD, PhD, FARVO. The journal covers a broad spectrum of work, including but not limited to: Applications of stem cell technology for regenerative medicine, Development of new animal models of human diseases, Tissue bioengineering, Chemical engineering to improve virus-based gene delivery, Nanotechnology for drug delivery, Design and synthesis of artificial extracellular matrices, Development of a true microsurgical operating environment, Refining data analysis algorithms to improve in vivo imaging technology, Results of Phase 1 clinical trials, Reverse translational ("bedside to bench") research. TVST seeks manuscripts from scientists and clinicians with diverse backgrounds ranging from basic chemistry to ophthalmic surgery that will advance or change the way we understand and/or treat vision-threatening diseases. TVST encourages the use of color, multimedia, hyperlinks, program code and other digital enhancements.