Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine & Health (FBMH), University of Manchester, Manchester M13 9PT, United Kingdom.
Division of Cardiovascular Sciences, School of Medical Sciences, FBMH, University of Manchester, Manchester M13 9PT, United Kingdom.
Mol Pharm. 2020 Jul 6;17(7):2390-2397. doi: 10.1021/acs.molpharmaceut.0c00151. Epub 2020 Jun 9.
Opticin is an endogenous vitreous glycoprotein that may have therapeutic potential as it has been shown that supranormal concentrations suppress preretinal neovascularization. Herein we investigated the pharmacokinetics of opticin following intravitreal injection in rabbits. To measure simultaneously concentrations of human and rabbit opticin, a selected reaction monitoring mass spectrometry assay was developed. The mean concentration of endogenous rabbit opticin in 7 uninjected eyes was measured and found to be 19.2 nM or 0.62 μg/mL. When the vitreous was separated by centrifugation into a supernatant and collagen-containing pellet, 94% of the rabbit opticin was in the supernatant. Intravitreal injection of human opticin (40 μg) into both eyes of rabbits was followed by enucleation at 5, 24, and 72 h and 7, 14, and 28 days postinjection ( = 6 at each time point) and measurement of vitreous human and rabbit opticin concentrations in the supernatant and collagen-containing pellet following centrifugation. The volume of distribution of human opticin was calculated to be 3.31 mL, and the vitreous half-life was 4.2 days. Assuming that rabbit and human opticin are cleared from rabbit vitreous at the same rate, opticin is secreted into the vitreous at a rate of 0.14 μg/day. We conclude that intravitreally injected opticin has a vitreous half-life that is similar to currently available antiangiogenic therapeutics. While opticin was first identified bound to vitreous collagen fibrils, here we demonstrate that >90% of endogenous opticin is not bound to collagen. Endogenous opticin is secreted by the nonpigmented ciliary epithelium into the rabbit vitreous at a remarkably high rate, and the turnover in vitreous is approximately 15% per day.
Opticin 是一种内源性玻璃体糖蛋白，具有治疗潜力，因为已经证明超正常浓度可以抑制视网膜前新生血管化。在此，我们研究了 Opticin 经玻璃体内注射后在兔体内的药代动力学。为了同时测量人源和兔源 Opticin 的浓度，开发了一种选择反应监测质谱分析测定法。测量了 7 只未注射眼的内源性兔源 Opticin 的平均浓度，发现为 19.2 nM 或 0.62 μg/mL。当玻璃体通过离心分离为上清液和含有胶原的沉淀时，94%的兔源 Opticin 在上清液中。将 40 μg 人源 Opticin 玻璃体内注射到兔双眼后，于注射后 5、24 和 72 小时以及 7、14 和 28 天（每个时间点 6 只眼）眼球摘除，并测量上清液和离心后的含胶原沉淀中的玻璃体中人源和兔源 Opticin 浓度。人源 Opticin 的分布容积计算为 3.31 mL，玻璃体半衰期为 4.2 天。假设兔源和人源 Opticin 以相同的速率从兔玻璃体中清除，Opticin 以 0.14 μg/天的速度分泌到玻璃体中。我们得出结论，玻璃体内注射的 Opticin 具有与目前可用的抗血管生成治疗药物相似的玻璃体半衰期。虽然 Opticin 最初被鉴定为与玻璃体胶原纤维结合，但在此我们证明 >90%的内源性 Opticin 不与胶原结合。内源性 Opticin 由非色素睫状上皮细胞以极高的速度分泌到兔玻璃体中，玻璃体的周转率约为每天 15%。
