白头翁皂苷B3的溶解度及油水分配系数与大鼠在体肠吸收研究

Solubility and oil-water partition coefficient of pulsatilla saponin B3 and its intestinal absorption in rats

目的测定白头翁皂苷B3的表观溶解度及油水分配系数,并研究其大鼠在体肠吸收机制。方法 HPLC-ELSD法测定B3的表观溶解度和油水分配系数,重量法计算大鼠在体单向肠灌流实验中吸收速率常数（Ka）和表观吸收系数（Papp）。结果白头翁皂苷B3在37℃有机溶剂中的表观溶解度较低,在碱性磷酸盐缓冲液中的表观溶解度较高;白头翁皂苷B3在不同磷酸盐缓冲液中的油水分配系数相差不大;白头翁皂苷B3在大鼠十二指肠、空肠、回肠和结肠的Ka和Papp没有显著性差异（P〉0.05）;白头翁皂苷B3在0.05-2.5 mg/mL随着浓度提高出现过饱和现象;加入P-糖蛋白抑制剂维拉帕米和P-糖蛋白底物地高辛后,都能显著提高白头翁皂苷B3的Ka值。结论在实验浓度范围内,溶解度和油水分配系数能够较好地预测肠吸收情况;白头翁皂苷B3不完全依赖浓度梯度转运,细胞膜上的载体蛋白参与了药物的转运过程,其小肠吸收机制并不完全为被动转运;受吸收部位影响较小,无特殊的吸收窗;P-糖蛋白介导了白头翁皂苷B3的小肠吸收。

Objective To determine the apparent solubility and Oil-water partition coefficient of B3 in total Pulsatilla saponin and to investigate its absorption mechanismin in rat intestines. Methods the apparent solubility and Oil-water partition coefficient of B3 was determined by HPLC-ELSD. Weight methods was employed to calculate the absorptive rate constants（Ka） and apparent absorption coefficient（Papp） of in situ rat intestinal perfusion model. Results the apparent solubility of B3 was higher in alkaline buffer solution than that in organic solvent at 37 ℃. Oil-water partition coefficients were close to each other in different phosphate buffer solutions at 37 ℃. There were no significant differences among the absorptive rate constants（Ka） and apparent absorption coefficient（Papp） of B3 in the four segments of the rat＇duodenum, jejunum, ileum and colon（P〉 0.05）. B3 displayed excessive satuation as the concentration increased over 0.05 - 2.5 mg·mL^-1. However, the Ka were significantly increased in the presence of P-glycoprotein（P-gP） inhibitor, verapamil and P-gP substrate, digoxin. Conclusion Solubility and oil-water partition coefficient can be used to predict the intestinal absorption. B3 didn＇t entirely transported in a concentration dependent manner, and the transporter-protein involved the transportation, so the intestinal absorption of B3 was not entirely passive diffusion; B3 were little influenced by absorption sites, there was no a preferential absorption zone in the intestine; The absorption and secretion of B3 are mediated by the efflux transport system, P-Gp.