| To provide some certain standards and ideas for the research of quantitative structure pharmacokinetic relationship (QSPKR) of muti-herbs remedy, a preliminary study on the impact of the pharmacokinetic properties of the ingredients in Chinese materia medica were conducted from the perspective of chemical structure firstly, based on the pre-study on Huan-Lian-Jie-Du Decoction (HLJDT), combing with the idea of QSPKR, its relating to the determination of the oil/ater partition coefficient and equilibrium solubility of the index components, the comparative pharmacokinetics of the components with same skeleton, and the impact of the pharmacokinetic properties of the indigrents in Chinese herbs by the body status and muti-herbs remedy conditions. The main research contents and results were as follows:(1) Taking pH variation of gastrointestinal of the body into consideration, the apparent oil/water partition coefficient (Kow) and equilibrium solubility of the compounds at different pH or pure water conditions were carried out by HPLC, and a preliminary analysis on the effects of absorption by the equilibrium solubility and apparent oil/water partition coefficient of the five indicators from the chemical structure perspective was conducted. The results showed that the equilibrium solubility of the components present the same skeleton with different substituting groups had a large difference, which of berberine itself had a small rate of change at the pH range of research, and the smallest and the largest at pH5.0and in pure water respectively; which of palmatine itself had a rising tendency with the increase of pH in general, and the rising rate was slow, to the maximum at pH8.0; which of baicalin had a rising tendency with the increase of pH in general too; which of baicalein and chrysin were less than O.lmg-mL-1that revealed extremely difficult to dissolve. The LogKow (the Logarithm of Kow) of berberine and palmatine were at range0-3and had a small rate of change at the pH range of research; the LogKow of baicalin, baicalein and chrysin were less than5.0and had large differences, the LogKow value decreased gradually with the increasing molecular weight under acidic conditions (pH<6.8), and that of chrysin and baicalein compared with baicalin under neutral and alkaline conditions but the LogKow value increased gradually with the increasing molecular weight on the terms of chrysin and baicalein. At the same time, the LogKow value showed a decreasing tendency in general on the terms of baicalin and chrysin, and a increasing trend firstly then decreasing on the terms of baicalein with the increasing pH.(2) The relationship of chemical structure and pharmacokinetic properties. For the index ingredients of Huang-Lian and Huang Qin comprising HLJDT example, the plasma samples were collected at different time points after administration of every monomer suspension liquid respectively, RP-HPLC was used to determine plasma levels of every index component, and DAS2.0software was used to simulate to the corresponding pharmacokinetic parameters, then the correlation between chemical structure and pharmacokinetic parameters was discussed preliminarily, and then the structure parameters which was contribute to pharmacokinetic properties were chosed from the perspective of the experimental research. The results showed that the hydrogenation degree of the C ring, the variety and quantity of substituent groups of the A ring of berberine and palmatine had effects upon their pharmacokinetic properties, and the chemical structure parameters which were contribute to pharmacokinetic properties from experimental research may include hydrogen bonding parameters, topology parameters and lipid/water partition coefficient; the steric configuration of substituent group in molecule, the number and sites of hydroxy of benzene ring, and the molecular forms and weight had correlation with pharmacokinetic properties of baicalin, baicalein and chrysin, the structural parameters which were contribute to pharmacokinetic properties from experimental research, including topology parameters, hydrogen bonding parameters, the lipid-water partition coefficient and molecular weight.(3) The influence of the body status on pharmacokinetic properties. For the index ingredients of Huang-Lian and Huang Qin comprising HLJDT example, the plasma samples were collected at different time points after administration of every monomer suspension liquid respectively after24h when the vascular dementia model of male SD rat was performed by electrocoagulation, RP-HPLC was used to determine plasma levels of every index component, and DAS2.0software was used to simulate to the corresponding pharmacokinetic parameters, then comparative pharmacokinetics of every pure component in nomal and model SD rats were conducted. To berberine, compared with nomal group, only t1/2z and Tmax had significant differences (P=0.037and0.008respectively),tl/2z were34.496±23.950VS27.272±13.004, Tmax were (2.257±1.784VS0.429±0.189); to palmatine, compared with nomal group, just Tmax had no significant difference (p=0.745), AUC(o-t) and Cmax were2.2and1.7times of normal group respectinvely (8507.187±1048.446VS4161.016±367.783and372.65±33.587VS218.907±49.997), and tl/2z was longer than normal group (23.956±4.397VS22.743±8.411); to baicalin, all the parameters which were simulated were more excellent than that of normal group, AUC(0-t), Cmax, MRT(o-t)and tl/2z were significant differences (P=0.042,0.036,0.009and0.024respectively) but Tmax had no signifi-cant difference (p=0.734), AUC(o-t), MRT(o-t), tl/2z and Cmax were1.48,1.11,1.96and1.3times of normal group respectinvely (98.948±29.092VS66.972+18.859,12.906±0.748VS11.618±0.706,19.00±10.638VS9.703±2.031and7.232±1.048VS5.459±1.620); to baicalein, jus t1/2z and MRT(o-t) presented significant differences (p=0.031and0.000respectively),tl/2z and MRT(o-t) were1.22and1.34times of normal group respectinvely (9.955±1.409VS8.151±1.306and12.422±1.118VS9.297±0.598); to chrysin, all the parameters which were simulated were more excellent than that of normal group, AUC(o-t), MRT(o-t) and Cmax were approximately2times of that of normal group (4.471±0.566VS2.209±0.643,38.982±2.867VS27.694±8.040and0.277±0.0811VS0.136±0.036respectively). And all the same time, the five pure components were presenting bimodal phenomenons regardless of the body status. The above results showed that there were different effects on pharmacokinetics of components which were with different structure.(4) The influence of the muti-herbs remedy conditions on pharmacokinetic properties were conducted to provide datas for adjusting QSPKR models of muti-herbs remedy conditions from monomers prespective. For HLJDT example, the plasma samples were collected at different time points after administration of HLJDT, RP-HPLC was used to determine plasma levels of every index component, and DAS2.0software was used to simulate to the corresponding pharma-cokinetic parameters, then comparative pharmacokinetics of every index component of HLJDT muti-herbs remedy to that of pure ingredients were carried out. The results showed that baicalin, berberine and palmatine of HLJDT demonstrated typical bimodal phenomenon in the plasma profiles, but baicalein of HLJDT displayed tri-model phenomenon in the plasma curve; it showed significant difference about the effects of muti-herbs remedy conditions on palmatine comparing with berberine, but the absorption state of berberine and palmatine of HLJDT were better than that of them used exclusively; the absorption state of baicalin and baicalein of HLJDT were more poor than that of them used exclusively.comparing monomers with them of HLJDT, AUC(o-∞) and Cmax of baicalin, baicalein and berberine were74.868±21.369VS13.549±2.171and5.459±1.620VS0.709±0.120μgmL-1,75.188±9.774VS1.589±0.932and5.604±0.436VS0.0369±0.009μg·mL-1,2502.599±436.419VS5888.57±1451.932and169.95±49.555VS371.723±86.233μg·L-1, respectively. |
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