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Intravitreal Pharmacokinetic Study of the Antiangiogenic Glycoprotein Opticin.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-05-21 , DOI: 10.1021/acs.molpharmaceut.0c00151 Eva M Del Amo 1 , John R Griffiths 2 , Izabela P Klaska 3 , Justin Hoke 3 , Anne White 4 , Leon Aarons 1 , Garth J S Cooper 2 , James W B Bainbridge 3 , Paul N Bishop 4, 5 , Richard D Unwin 2, 6
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-05-21 , DOI: 10.1021/acs.molpharmaceut.0c00151 Eva M Del Amo 1 , John R Griffiths 2 , Izabela P Klaska 3 , Justin Hoke 3 , Anne White 4 , Leon Aarons 1 , Garth J S Cooper 2 , James W B Bainbridge 3 , Paul N Bishop 4, 5 , Richard D Unwin 2, 6
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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 (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 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.
中文翻译：
抗血管生成糖蛋白Opticin的玻璃体内药代动力学研究。
视蛋白是一种内源性玻璃体糖蛋白，可能具有治疗潜力，因为已经证明超浓度可抑制视网膜前新生血管形成。在本文中，我们研究了玻璃体腔内注射兔后视黄质的药代动力学。为了同时测量人和兔视黄蛋白的浓度，开发了一种选择的反应监测质谱分析法。测量了7只未注射眼中内源性兔视黄蛋白的平均浓度，发现为19.2 nM或0.62μg/ mL。当通过离心将玻璃体分离成上清液和含胶原的沉淀时，上清液中有94％的兔视黄蛋白。在兔子的两只眼中玻璃体内注射人类视黄蛋白（40μg），然后在注射后第5、24、72 h和第7、14、28天摘除（ñ在每个时间点= 6），并在离心后测量上清液和含胶原的沉淀物中玻璃体中人和兔视黄蛋白的浓度。人视黄蛋白的分布体积经计算为3.31mL，玻璃体半衰期为4.2天。假设兔子和人的视黄蛋白以相同的速率从兔玻璃体中清除，视黄蛋白以0.14μg/天的速率分泌到玻璃体中。我们得出结论，玻璃体内注射的视黄蛋白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。虽然最初发现视蛋白是与玻璃状胶原原纤维结合的，但在这里我们证明了> 90％的内源性视蛋白未与胶原蛋白结合。内源性视蛋白由非色素性睫状上皮分泌到兔玻璃体中的速率非常高，
更新日期：2020-07-06
中文翻译：
抗血管生成糖蛋白Opticin的玻璃体内药代动力学研究。
视蛋白是一种内源性玻璃体糖蛋白，可能具有治疗潜力，因为已经证明超浓度可抑制视网膜前新生血管形成。在本文中，我们研究了玻璃体腔内注射兔后视黄质的药代动力学。为了同时测量人和兔视黄蛋白的浓度，开发了一种选择的反应监测质谱分析法。测量了7只未注射眼中内源性兔视黄蛋白的平均浓度，发现为19.2 nM或0.62μg/ mL。当通过离心将玻璃体分离成上清液和含胶原的沉淀时，上清液中有94％的兔视黄蛋白。在兔子的两只眼中玻璃体内注射人类视黄蛋白（40μg），然后在注射后第5、24、72 h和第7、14、28天摘除（ñ在每个时间点= 6），并在离心后测量上清液和含胶原的沉淀物中玻璃体中人和兔视黄蛋白的浓度。人视黄蛋白的分布体积经计算为3.31mL，玻璃体半衰期为4.2天。假设兔子和人的视黄蛋白以相同的速率从兔玻璃体中清除，视黄蛋白以0.14μg/天的速率分泌到玻璃体中。我们得出结论，玻璃体内注射的视黄蛋白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。虽然最初发现视蛋白是与玻璃状胶原原纤维结合的，但在这里我们证明了> 90％的内源性视蛋白未与胶原蛋白结合。内源性视蛋白由非色素性睫状上皮分泌到兔玻璃体中的速率非常高，
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