Song Im-Sook, Nam So-Jeong, Jeon Ji-Hyeon, Park Soo-Jin, Choi Min-Koo
BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, Vessel-Organ Interaction Research Center (VOICE), Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Korea.
College of Korean Medicine, Daegu Haany University, Daegu 38610, Korea.
Pharmaceutics. 2021 Apr 28;13(5):628. doi: 10.3390/pharmaceutics13050628.
We evaluated the bioavailability, liver distribution, and efficacy of silymarin-D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) solid dispersion (silymarin-SD) in rats with acetaminophen-induced hepatotoxicity (APAP) compared with silymarin alone. The solubility of silybin, the major and active component of silymarin, in the silymarin-SD group increased 23-fold compared with the silymarin group. The absorptive permeability of silybin increased by 4.6-fold and its efflux ratio decreased from 5.5 to 0.6 in the presence of TPGS. The results suggested that TPGS functioned as a solubilizing agent and permeation enhancer by inhibiting efflux pump. Thus, silybin concentrations in plasma and liver were increased in the silymarin-SD group and liver distribution increased 3.4-fold after repeated oral administration of silymarin-SD (20 mg/kg as silybin) for five consecutive days compared with that of silymarin alone (20 mg/kg as silybin). Based on higher liver silybin concentrations in the silymarin-SD group, the therapeutic effects of silymarin-SD in hepatotoxic rats were evaluated and compared with silymarin administration only. Elevated alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels were significantly decreased by silymarin-SD, silymarin, and TPGS treatments, but these decreases were much higher in silymarin-SD animals than in those treated with silymarin or TPGS. In conclusion, silymarin-SD (20 mg/kg as silybin, three times per day for 5 days) exhibited hepatoprotective properties toward hepatotoxic rats and these properties were superior to silymarin alone, which may be attributed to increased solubility, enhanced intestinal permeability, and increased liver distribution of the silymarin-SD formulation.
我们评估了水飞蓟宾 - D-α-生育酚聚乙二醇1000琥珀酸酯（TPGS）固体分散体（水飞蓟素 - SD）在对乙酰氨基酚诱导的肝毒性（APAP）大鼠中的生物利用度、肝脏分布及疗效，并与单独使用水飞蓟素进行比较。水飞蓟素的主要活性成分水飞蓟宾在水飞蓟素 - SD组中的溶解度相较于水飞蓟素组增加了23倍。在TPGS存在的情况下，水飞蓟宾的吸收渗透率增加了4.6倍，其外排率从5.5降至0.6。结果表明，TPGS通过抑制外排泵发挥增溶剂和渗透促进剂的作用。因此，连续5天重复口服水飞蓟素 - SD（以水飞蓟宾计20 mg/kg）后，水飞蓟素 - SD组血浆和肝脏中的水飞蓟宾浓度增加，肝脏分布相较于单独使用水飞蓟素（以水飞蓟宾计20 mg/kg）增加了3.4倍。基于水飞蓟素 - SD组肝脏中水飞蓟宾浓度更高，评估了水飞蓟素 - SD对肝毒性大鼠的治疗效果，并与仅给予水飞蓟素进行比较。水飞蓟素 - SD、水飞蓟素和TPGS治疗均显著降低了升高的丙氨酸转氨酶、天冬氨酸转氨酶和碱性磷酸酶水平，但水飞蓟素 - SD处理的动物中这些降低幅度远高于水飞蓟素或TPGS处理的动物。总之，水飞蓟素 - SD（以水飞蓟宾计20 mg/kg，每日3次，共5天）对肝毒性大鼠具有保肝特性，且这些特性优于单独使用水飞蓟素，这可能归因于水飞蓟素 - SD制剂的溶解度增加、肠道通透性增强以及肝脏分布增加。
