给药补骨脂提取物后大鼠体内补骨脂素、异补骨脂素、补骨脂苷及异补骨脂苷的药代动力学研究

Pharmacokinetic characteristics of psoralen,isopsoralen,psoralenoside and isopsoralenoside in rats after oral administration of Psoraleae Fructus extract

香豆素是中药补骨脂中的与其药效相关的主要活性成分,为了开展补骨脂的多成分药代动力学研究,建立了一种能够灵敏、快速一同检测给药后大鼠血浆中补骨脂素、异补骨脂素、补骨脂苷和异补骨脂苷的液相色谱-质谱联用定量分析方法,并对该分析方法进行了方法学验证。随后将该方法用于单次和多次给药补骨脂提取物后大鼠体内补骨脂素、异补骨脂素、补骨脂苷及异补骨脂苷的药代动力学研究。结果表明,大鼠单次灌胃给药补骨脂提取物后,补骨脂素和异补骨脂素的暴露相对较高,AUC0-∞分别为443 619~582 680、167 314~276 903 ng·mL^(-1)·h^(-1),补骨脂苷和异补骨脂苷的暴露相对较低,但存在明显的性别差异,雄高雌低,可能与补骨脂苷和异补骨脂苷极性较大不易透过吸收有关;大鼠连续7 d灌胃给药补骨脂提取物后,补骨脂素和异补骨脂素的AUC0-∞分别为29 701~81 783、39 234~89 914 ng·mL^(-1)·h^(-1),较第1天给药后的AUC0-∞明显降低(P<0.05);大鼠连续7 d灌胃给药补骨脂提取物后,补骨脂苷和异补骨脂苷的AUC0-∞分别为7 360~19 342、8 823~45 501 ng·mL^(-1)·h^(-1),雌雄大鼠体内的AUC0-∞没有明显的性别差异,但雄性大鼠较第1天给药后的AUC0-∞明显降低(P<0.05),且t1/2和MRT变短,表明这2个化合物从体内的清除加快。

Coumarins are the main active components in Psoraleae Fructus. To study the multi-component pharmacokinetics of Psoraleae Fructus, this study established a sensitive and rapid ultra-pressure liquid chromatography coupled to tandem mass spectrometry(UPLC-MS/MS) method for simultaneous determination of psoralen, isopsoralen, psoralenoside, and isopsoralenoside in rat plasma. After validation, the method was applied to the investigation of pharmacokinetics of psoralen, isopsoralen, psoralenoside, and isopso-ralenoside in rats after single and multiple administration of Psoraleae Fructus extract. The results revealed that the exposure of psoralen and isopsoralen in rat plasma was high after a single intragastric administration of Psoraleae Fructus extract, with an AUC0-∞ of 443 619-582 680 and 167 314-276 903 ng·mL^(-1)·h^(-1), respectively. Compared with these two compounds, the exposure of psoralenoside and isopsoralenoside was lower with marked gender difference. After 7-day administration of Psoraleae Fructus extract to rats, the AUC0-∞ of psoralen and isopsoralen was 29 701-81 783 and 39 234-89 914 ng·mL^(-1)·h^(-1), respectively, which was significantly lower than that at the first day(P<0.05), and that of psoralenoside and isopsoralenoside was 7 360-19 342 and 8 823-45 501 ng·mL^(-1)·h^(-1), respectively. There was no significant gender difference in exposure of psoralenoside and isopsoralenoside in male and female rats. However, the exposure of psoralenoside and isopsoralenoside in male rats was reduced(P<0.05), and the t1/2 and mean residence time(MRT) were shortened, suggesting that the removal of these two compounds from the body was accelerated.