黄豆苷元磷脂复合物的制备及大鼠体内生物利用度的研究

Preparation of Daidzein-Phospholipid Complex and Its Bioavailability Study in Rats

目的制备黄豆苷元磷脂复合物并测定其在大鼠体内的生物利用度。方法以黄豆苷元与大豆磷脂的复合率为评价指标,采用单因素试验和正交设计优化制备工艺;分别测定黄豆苷元、黄豆苷元-磷脂的物理混合物及黄豆苷元磷脂复合物在水中和正辛醇中的表观溶解度;3组大鼠分别灌胃给予黄豆苷元原料药、黄豆苷元-磷脂的物理混合物及黄豆苷元磷脂复合物后,采用LC-MS/MS测定不同时间血浆中药物浓度,比较相对生物利用度。结果黄豆苷元磷脂复合物优化的制备条件为:反应溶剂为无水乙醇,投料比为1.5∶1(磷脂/药物的摩尔比),1g·L-1反应物浓度条件下60℃搅拌2h,结果显示:磷脂复合物在水和正辛醇中表观溶解度比原料药分别提高3.1倍和5.4倍;大鼠灌胃给予黄豆苷元和黄豆苷元磷脂复合物后,Cmax分别为(667±65),(7509±688)ng·mL-1,Tmax分别为(3.00±0.82),(0.42±0.17)h,AUC0–∞分别为(8302±590),(28870±2411)ng·h·mL-1。黄豆苷元磷脂复合物口服生物利用度是黄豆苷元原料药的3.48倍。结论将黄豆苷元制成磷脂复合物后在水中的溶解度有所提高,在正辛醇中的溶解度有显著提高,增加了黄豆苷元在胃肠道中的吸收,明显提高黄豆苷元口服生物利用度。

OBJECTIVE To optimize preparation methods of daidzein-phospholipid complex and determine its bioavailability in rats after oral administration. METHODS Using binding ratio of daidzein to phospholipid as evaluation parameter, the preparation methods for daidzein-phospholipid complex were optimized by means of single factor tests and orthogonal design. Apparent solubility of daidzein, physical mixture and daidzein-phospholipid complex in water and n-octanol was determined, respectively. The concentrations of daidzein in plasma samples in rats were analysed by LC-MS/MS after oral administration of daidzein suspension, physical mixture and daidzein-phospholipid complex, and their bioavailabilities were compared. RESULTS The daidzein-phospholipid complex was prepared by stirring and refluxing phospholipid Epikuron 200 and daidzein （molar ratio 1.5∶1） in ethanol at a temperature of 60 ℃ for 2 h. Apparent solubility of daidzein-phospholipid complex were 3.1 and 5.4 folds compared with daidzein in water and n-octanol, respectively. Pharmacokinetic parameters of Cmax were （667±65） ng·mL^-1 and （7 509±688）ng·mL^-1, Tmax were （3.00±0.82）h and （0.42±0.17）h,AUC0–∞ were （8 302±590）ng·h·mL^-1 and （28 870± 2 411）ng·h·mL^-1 after oral administration of daidzein suspension and daidzein-phospholipid complex in rats, respectively. The relative bioavailability of daidzeinphospholipid complex to daidzein was 3.48. CONCLUSION Apparent solubility of daidzeinphospholipid complex both in water and n-octanol were improved, thus, increasing gastrointestinal absorption. As a result, the bioavailability was increased after oral administration of daidzein-phospholipid complex in rats.