Metabolism, Excretion and Bioavailability of Hydroxysafflor Yellow A after Oral Administration of Its Lipid-Based Formulation and Aqueous Solution in Rats

AimTo characterize the effect of different oral formulations on the metabolism, excretion and bioavailability of hydroxysafflor yellow A (HSYA).MethodsHSYA lipid-based formulation and aqueous solution were prepared and orally administered to rats. A gradient HPLC and LC-MS method was performed to determine HSYA concentration in rat serum, bile, urine and feces samples.ResultsThe bile sample digestion test combining HPLC with LC-MS proved the existence of HSYA and phase II metabolites in bile for both formulations. Their protonated molecular ions at m/z 918 and m/z 691 indicated that the metabolites were glutathione and sulfate conjugate, according to the protonated molecular ions of HSYA at m/z 611. The amount of the two metabolites and HSYA excreted from bile was significantly decreased for the lipid-based formulation, compared with that of the aqueous solution. The amount of parent component, HSYA, in bile, feces and urine in 24 h was (0.05 ± 0.03)%, (8.80 ± 2.30)% and (37.99 ± 17.50)% for the lipid-based formulation. For the aqueous solution, the amount of HSYA excreted in bile, feces and urine in 24 h was (0.32 ± 0.22)%, (44.66 ± 8.00)% and (5.58 ± 1.30)%, respectively. Compared with the cmax of 0.08 μg·mL−1 and AUC0–8 h of 10.73 μg·min·mL−1 for HSYA aqueous solution, the cmax and AUC0–8 h of HSYA lipid-based formulation were significantly increased up to 2.79 μg·mL−1 and 402.51 μg·min·mL−1.ConclusionThe results suggested that the lipid-based formulation may not alter the phase II metabolism mechanism of HSYA but significantly decreased HSYA excretion from bile and feces so as to enhance the bioavailability and absorption.

摘 要目的：研究不同的羟基红花黄色素A（HSYA）剂型对HSYA代谢、排泄、生物利用度的影响。方法：大鼠灌胃给予HSYA脂质制剂和水溶液，采用HPLC及LC-MS检测血浆、胆汁、粪便、尿液样品。结果：大鼠灌胃给予HSYA脂质制剂和水溶液后，在大鼠胆汁中均发现HSYA及其II相代谢产物; HSYA原药的质荷比为611，而两个II相代谢产物的质荷比分别为918和691，结合酶降解实验表明这两个代谢产物分别为HSYA的谷胱甘肽结合物和硫酸酯结合物。但是同水溶液相比，HSYA脂质制剂显著性降低了HSYA及其II相代谢产物从胆汁的排泄量。大鼠灌胃给予HSYA脂质制剂后，HSYA原药从胆汁、粪便、尿液中24 h的累积排泄量分别为(0.05 ± 0.03)%、(8.80 ± 2.30)%、(37.99 ± 17.50)%，其cmax、AUC0-8 h分别为2.79 μg·mL−1、402.51 μg·min·mL−1; 而大鼠灌胃给予HSYA水溶液后，HSYA原药从胆汁、粪便、尿液中24 h的累积排泄量分别为(0.32 ± 0.22)%、(44.66 ± 8.00)%、(5.58 ± 1.30)%, 其cmax、AUC0-8 h 分别为0.08 μg·mL−1、10.73 μg·min·mL−1。结论：实验结果表明脂质制剂可能不会改变HSYA的代谢机制，但是显著性降低了HSYA从粪便和胆汁的排泄量，提高了其生物利用度。