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(K_a)和表观吸收系数(P_app)。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K_a和P_app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K_a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 (K_a) and apparent absorption coefficient (P_app) 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 (K_a) and apparent absorption coefficient (P_app) 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 K_a 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.

江西省重大科技专项——生物和新医药产业发展关键技术研究(2010AZD00301);江西省青年科学基金计划(20132BAB215029);江西省教育厅科学技术研究项目(GJJ14621,GJJ12529);江西省科技支撑计划(20141BBG70077);江西省研究生创新专项资金项目(YC2013-S235)