目的 測定白頭翁皂苷B3的表觀溶解度及油水分配系數(shù),并研究其大鼠在體腸吸收機制。方法 HPLC-ELSD法測定B3的表觀溶解度和油水分配系數(shù),重量法計算大鼠在體單向腸灌流實驗中吸收速率常數(shù)(K_a)和表觀吸收系數(shù)(P_app)。結果 白頭翁皂苷B3在37℃有機溶劑中的表觀溶解度較低,在堿性磷酸鹽緩沖液中的表觀溶解度較高;白頭翁皂苷B3在不同磷酸鹽緩沖液中的油水分配系數(shù)相差不大;白頭翁皂苷B3在大鼠十二指腸、空腸、回腸和結腸的K_a和P_app沒有顯著性差異(P > 0.05);白頭翁皂苷B3在0.05~2.5 mg/mL隨著濃度提高出現(xiàn)過飽和現(xiàn)象;加入P-糖蛋白抑制劑維拉帕米和P-糖蛋白底物地高辛后,都能顯著提高白頭翁皂苷B3的K_a值。結論 在實驗濃度范圍內,溶解度和油水分配系數(shù)能夠較好地預測腸吸收情況;白頭翁皂苷B3不完全依賴濃度梯度轉運,細胞膜上的載體蛋白參與了藥物的轉運過程,其小腸吸收機制并不完全為被動轉運;受吸收部位影響較小,無特殊的吸收窗;P-糖蛋白介導了白頭翁皂苷B3的小腸吸收。

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.

江西省重大科技專項——生物和新醫(yī)藥產業(yè)發(fā)展關鍵技術研究(2010AZD00301);江西省青年科學基金計劃(20132BAB215029);江西省教育廳科學技術研究項目(GJJ14621,GJJ12529);江西省科技支撐計劃(20141BBG70077);江西省研究生創(chuàng)新專項資金項目(YC2013-S235)