THE MOLECULAR BASIS OF DRUG-PLASMA PROTEIN INTERACTION FOR CNS ACTIVE COMPOUNDS

D. Obradović, Mila Radan, Marija R. Popović-Nikolić, Slavica Oljacic, K. Nikolić
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Abstract

The human serum albumin (HSA) is well known for its extraordinary binding capacity for both endogenous and exogenous compounds, including a wide range of drugs. The goal of our investigation was to evaluate the distribution process for 15 CNS active compounds. The drug-plasma protein interaction was evaluated under simulative physiological conditions on the HSA-based stationary phase by using the mixture of Sørensen phosphate buffer (pH 7.40) and acetonitrile modifier as a mobile phase (84:16 v/v). The retention parameters (k) were used to approximate the % of protein-binding by calculating the P(%) values. The results obtained through this study demonstrated that the constitutional properties (e.g. number of total bonds, atoms, carbon atoms) and lipophilicity have a strong positive impact on the HSA-binding affinity. The coefficient of diffusion has a negative impact, while the atoms and sites available for the CYP450 oxidation showed the most significant correlation (r = 0.92). This study provides a basis for further in vitro chromatographical investigations of drug-HSA interaction for CNS active compounds. The correlation between obtained retention data and the availability to enzymes oxidation indicates the application of the tested system in the assessment of the metabolic degradation profile of CNS related drugs.
CNS活性化合物药物-血浆蛋白相互作用的分子基础
人血清白蛋白(HSA)以其对内源性和外源性化合物(包括多种药物)的非凡结合能力而闻名。我们研究的目的是评价15种中枢神经系统活性化合物的分布过程。以Sørensen磷酸盐缓冲液(pH 7.40)和乙腈改性剂的混合物为流动相(84:16 v/v),在模拟生理条件下,在基于hsa的固定相上评估药物与血浆蛋白的相互作用。保留参数(k)通过计算P(%)值来近似蛋白质结合的百分比。通过本研究得到的结果表明,结构性质(如总键数、原子数、碳原子数)和亲脂性对hsa结合亲和力有很强的正向影响。扩散系数有负向影响,而CYP450氧化可用的原子和位点的相关性最显著(r = 0.92)。本研究为进一步开展CNS活性化合物与hsa相互作用的体外色谱研究奠定了基础。所获得的保留数据与酶氧化可用性之间的相关性表明了所测试系统在评估中枢神经系统相关药物代谢降解概况中的应用。
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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