Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Republic of Korea.
Ophthalmic Res. 2020;63(1):41-49. doi: 10.1159/000499529. Epub 2019 May 21.
This study was aimed at determining the intraocular pharmacokinetics based on molecular physicochemical properties in a rabbit model.
The entire dataset was obtained from previous literature, and research articles regarding 70 molecular compounds were investigated. The intravitreal half-lives in rabbit eyeballs of 22 macromolecules and 48 micromolecules were analyzed. Multiple linear regression analysis was carried out with non-collinear independent variables (molecular weight [MW] and lipophilicity) influencing intravitreal half-lives. The best-fit equations were selected based on the correlation coefficients and goodness-of-fit statistics.
The best-fit models obtained from the entire dataset, macromolecules, and micromolecules suggest the correlation between molecular physicochemical properties (MW and lipophilicity) and intravitreal half-life. Exclusion of outlier molecules (amphotericin B and foscarnet) leads to a better-fit correlation. MW is the definite single factor affecting intravitreal half-lives of macromolecules (Log t1/2 = 0.148 + 0.370 Log MW, R2 = 0.769), while both MW and lipophilicity influence the intraocular pharmacokinetics of micromolecules (Log t1/2 = -1.213 + 0.762 Log MW - 0.115 Log p, R2 = 0.554).
The present study indicates that intravitreal half-life could be predicted based on molecular physicochemical properties (MW and lipophilicity). Also, increasing MW while reducing lipophilicity would be a reliable method for prolonging the intravitreal half-life of small chemical drugs, while MW is the single major determinant for large biologic drugs.
本研究旨在通过兔模型确定基于分子物理化学特性的眼内药代动力学。
整个数据集均来自先前的文献，对 70 种分子化合物的研究文章进行了调查。分析了 22 种大分子和 48 种小分子在兔眼球内的半衰期。用影响眼内半衰期的非共线性独立变量（分子量[MW]和脂溶性）进行多元线性回归分析。根据相关系数和拟合优度统计选择最佳拟合方程。
从整个数据集、大分子和小分子获得的最佳拟合模型表明，分子物理化学特性（MW 和脂溶性）与眼内半衰期之间存在相关性。排除异常分子（两性霉素 B 和膦甲酸）会导致相关性更好。MW 是影响大分子眼内半衰期的唯一因素（Log t1/2=0.148+0.370 Log MW，R2=0.769），而 MW 和脂溶性均影响小分子的眼内药代动力学（Log t1/2=-1.213+0.762 Log MW-0.115 Log p，R2=0.554）。
本研究表明，眼内半衰期可根据分子物理化学特性（MW 和脂溶性）进行预测。此外，增加 MW 同时降低脂溶性是延长小分子化学药物眼内半衰期的可靠方法，而 MW 是大分子生物药物的单一主要决定因素。
