Sztanke Małgorzata, Tuzimski Tomasz, Janicka Małgorzata, Sztanke Krzysztof
Chair and Department of Medical Chemistry, Medical University of Lublin, 4A Chodźki Street, 20-093 Lublin, Poland.
Department of Physical Chemistry, Chair of Chemistry, Faculty of Pharmacy with Medical Analytics Division, Medical University of Lublin, 4A Chodźki Street, 20-093 Lublin, Poland.
Eur J Pharm Sci. 2015 Feb 20;68:114-26. doi: 10.1016/j.ejps.2014.12.011. Epub 2014 Dec 17.
The chromatographic behaviour and significant lipophilicity/hydrophobicity indices (log k(w), S, φ(0)) are presented for 21 biologically active fused 1,2,4-triazinones based on the linear relationship: log k = log k(w)-Sφ established for the retention on LC-18 HPLC column, using as mobile phases mixtures of three organic modifiers with water. The effect of these mobile phase modifiers on the chromatographic behaviour of solutes was established and the organic modifier of choice is suggested. The complex correlation of slopes versus intercepts obtained for acetonitrile, contrary to linear ones obtained for methanol and dioxane are disclosed. The observed difference in retention mechanism for acetonitrile compared to methanol and dioxane is explained by intermolecular interactions encoded in lipophilicity. Linear correlations with statistically significant levels between log kw values determined from three different chromatographic systems were obtained. The relationships between log k(w) constants (derived from the linear model for methanol-water mobile phases) and predicted log P and log S values by the use of various computational methods were investigated and these were established with high correlation coefficients. The predicted log P values plotted against φ(0 (MeOH)) indices showed the best fit. Principal component analysis was used to compare various lipophilicity parameters of the solutes and their in silico biological descriptors relevant to optimal pharmacokinetics profile. The similarities and dissimilarities between all the variables and molecular structures of solutes are presented. Statistically significant correlations were found between the chromatographic lipophilicity indices and the calculated pharmacokinetic descriptors: fraction unbound in brain (f(u, brain)), oral bioavailability (%F), permeability and intestinal absorption in jejunum (Caco-2), skin permeation (log K(p)) and blood/brain concentration (log BB).
基于在LC - 18高效液相色谱柱上的保留所建立的线性关系log k = log k(w) - Sφ，给出了21种具有生物活性的稠合1,2,4 - 三嗪酮的色谱行为以及重要的亲脂性/疏水性指数（log k(w)、S、φ(0)），其中使用三种有机改性剂与水的混合物作为流动相。确定了这些流动相改性剂对溶质色谱行为的影响，并提出了首选的有机改性剂。揭示了与甲醇和二氧六环获得的线性关系相反，乙腈获得的斜率与截距的复杂相关性。通过亲脂性中编码的分子间相互作用解释了乙腈与甲醇和二氧六环相比在保留机制上观察到的差异。获得了由三种不同色谱系统测定的log kw值之间具有统计学显著水平的线性相关性。研究了log k(w)常数（源自甲醇 - 水流动相的线性模型）与使用各种计算方法预测的log P和log S值之间的关系，并以高相关系数建立了这些关系。针对φ(0 (MeOH))指数绘制的预测log P值显示出最佳拟合。主成分分析用于比较溶质的各种亲脂性参数及其与最佳药代动力学特征相关的计算机模拟生物学描述符。展示了所有变量与溶质分子结构之间的异同。发现色谱亲脂性指数与计算的药代动力学描述符之间存在统计学显著相关性：脑内未结合分数（f(u, brain)）、口服生物利用度（%F）、空肠中的渗透性和肠道吸收（Caco - 2）、皮肤渗透性（log K(p)）以及血脑浓度（log BB）。
