构建了定量结构-保留关系(QSRR)测定马兜铃酸A、马兜铃酸B、马兜铃内酰胺及白黎芦醇的正辛醇-水分配系数(Kow).采用反相高效液相色谱(RP-HPLC)法,以甲醇-水为流动相,以16种已知Kow值的酸性和中性苯系物为模型化合物,以保留时间两点校正法(DP-RTC)校正保留时间,并由Snyder-Soczewinski方程得100%水相保留因子kw,建立了表观正辛醇-水分配系数Kow″与kw的定量关系(QSRR模型),并对模型进行了内、外部验证.结果显示,不同pH下的QSRR模型线性相关性良好(相关系数R2为0.980~0.987),内部验证(交叉验证相关系数R2cv为0.982~0.988)和外部验证结果(6种验证化合物的相对误差RE为0.6%~10.9%)令人满意.将建立的QSRR模型应用于中药中4种潜在肝肾毒性化合物的Kow测定,并与软件计算值、摇瓶法(SFM)实验值比较,结果显示该方法准确性更高,且简单快捷.该文提出的采用中性及酸性苯系物建立QSRR模型,通过对结构与性质相似的中药材组分进行RP-HPLC分析,得到各待测组分的保留时间即可获得其Kow值的简便策略,解决了中药组分复杂且难以分离、无法通过SFM测定其Kow值的问题,为通过定量-构效关系(QSAR)模型实现快速预测中药组分的肝肾毒性提供了可靠的Kow数据.
A quantitative structure-retention relationship (QSRR) was proposed to determine n-octanol-water partition coefficients (Kow) of aristolochic acid A, aristolochic acid B, aristololactam and resveratrol in this paper.Sixteen acidic and neutral benzene analogues with reliable experimental Kow data were chosen as model compounds for establishing linear relationship between the apparent n-octanol-water partition coefficient (Kow″) and retention factor of 100% aqueous phase (kw), which corresponds to retention factors of solutes using neat aqueous fraction as mobile phase.Methanol-water mixture was used as mobile phase at various mobile phase pH, and retention time (tR) was rectified by a dual-point retention time correction (DP-RTC).The established models were evaluated by internal and external validations, respectively.QSRR models had good correlation coefficients at different mobile phase pH with correlation coefficients (R2) ranged from 0.980 to 0.987.Both internal (the cross-validated correlation coefficients (R2cv) of 0.982-0.988) and external (0.6%≤relative errors (RE)≤10.9% for all the six verification compounds) validations showed satisfactory results.Kow values of four hepatotoxic/nephrotoxic ingredients in traditional herbs were predicted by QSRR, and compared with the ones obtained by shake-flask method (SFM) and calculated by software as well.The method provided a convenient and rapid way to obtain reliable Kow data.In addition, the proposed protocol realized simultaneous prediction for Kow values of structure-similar components in traditional herbs merely through retention times, thereupon solved the dilemma of Kow measurement by SFM resulting from inaccessibility of separating single component from complex herbs.These Kow data can be applied in toxicity prediction of components in traditional herbs through quantitative structure-activity relationships (QSARs) in a follow-up study.
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