Intravitreal Pharmacokinetic Study of the Antiangiogenic Glycoprotein Opticin
Intravitreal Pharmacokinetic Study of the Antiangiogenic Glycoprotein Opticin
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DOI：
10.1021/acs.molpharmaceut.0c00151
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发表时间：
2020-07-06
影响因子：
4.9
通讯作者：
Unwin, Richard D.
中科院分区：
文献类型：
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作者：
del Amo, Eva M.;Griffiths, John R.;Unwin, Richard D.
视黄素是一种内源性玻璃体糖蛋白，它可能具有治疗潜力，因为已有研究表明，超常浓度抑制视网膜前新生血管。在此，我们研究了兔玻璃体内注射视黄素的药代动力学。为了同时测定人和兔视黄素的浓度，建立了一种选择性反应监测质谱法。7只未注射眼测得兔内源性视黄素平均浓度为19.2 nM或0.62微克/毫升。用离心法将玻璃体分离成上清液和含胶原蛋白的小球，上清液中含有94%的兔视蛋白。分别于注射后5、24、72 h、7、14、28 d(各时间点6只)玻璃体腔内注射人视蛋白(40 MU G)，离心后测定上清液和胶原颗粒中人和兔玻璃体视蛋白浓度。人视黄素的分布体积为3.31毫升，玻璃体半衰期为4.2天。假设兔和人的视黄素以相同的速度从兔玻璃体中清除，视黄素以0.14微克/天的速度分泌到玻璃体中。我们得出结论，玻璃体内注射视黄素的玻璃体半衰期与目前可用的抗血管生成治疗药物相似。虽然视黄素最初被鉴定为与玻璃体胶原纤维结合，但我们在这里证明了90%的内源性视黄素不与胶原结合。内源性视黄素由无色素的睫状体上皮以极高的速度分泌到兔的玻璃体内，玻璃体内的周转率约为每天15%。
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 mu g/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 mu g) into both eyes of rabbits was followed by enucleation at 5, 24, and 72 h and 7, 14, and 28 days postinjection (n = 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 mu g/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.