川芎中阿魏酸和藁本内酯的肠吸收特性分析

Analysis of Intestinal Absorption Characteristics of Ferulic Acid and Ligustilide in Chuanxiong Rhizoma

目的:研究川芎中阿魏酸和藁本内酯在不同肠段的吸收特征,探索指标成分单体和川芎提取物使用时的吸收变化,考察P-糖蛋白(P-gp)和多药耐药相关蛋白(MRP)对这2个成分吸收的影响。方法:采用大鼠单向肠灌流模型,利用UHPLC测定灌流液中阿魏酸和藁本内酯的含量变化,分析二者在各肠段、川芎提取物不同质量浓度及含蛋白抑制剂情况下的含量变化情况,计算吸收速率参数(Ka)和有效渗透系数(Peff)。结果:阿魏酸与藁本内酯在肠道各段均有吸收,藁本内酯的吸收大于阿魏酸。阿魏酸在十二指肠的Ka=1.23×10^(-3)s^(-1),与空肠和回肠的吸收无显著性差异。阿魏酸在生药质量浓度12.5,20.0,40.0 g·L^(-1)下的吸收无显著性差异,但100.0 g·L^(-1)下的吸收较前3个质量浓度显著降低。阿魏酸在提取物中的吸收明显高于单体直接灌流,与川芎提取物组比较,丙磺舒组的阿魏酸吸收显著性增加。藁本内酯在十二指肠的Ka=3.58×10^(-3)s^(-1),肠道的吸收大小排序为回肠>十二指肠≈空肠>结肠,吸收随川芎提取物质量浓度的增加而降低。与川芎提取物组比较,藁本内酯在维拉帕米组和丙磺舒组的吸收均显著性增加,且丙磺舒组的吸收大于维拉帕米组。结论:阿魏酸吸收方式可能为促进扩散,存在载体参与,为MRP的底物。藁本内酯主要依靠载体的主动转运,可能是P-gp与MRP的底物,且受MRP影响更大。

Objective： To investigate absorption characteristics of ferulic acid and ligustilide in Chuanxiong Rhizoma at different intestinal segment, and to explore the absorption changes of monomer and herbal extract, then to investigate the influence of P-glycoprotein （P-gp） and multidrug resistance-associated protein （MRP） on absorption of these two ingredients. Method： In situ single pass intestinal perfusion model was used and the change of concentration of ferulic acid and ligustilide were determined by UHPLC at various intestinal segments, different concentration of herbal extract, containing protein inhibitor, their absorption rate parameters （Ka） and effective permeability coefficients （Poff） were calculated. Result： Ferulic acid and ligustilide were absorbed in all intestinal segments, the absorption of ligustilide was better than ferulic acid. The Ka of ferulic acid in the duodenum was 1.23 × 10 -3 s-1 and there was no significant difference in the jejunum and ileum. There was no significant difference about the absorption of ferulic acid in concentration of herbal extract with 12.5, 20. 0,40.0 g.L-1, but the absorption at 100 g × L-1 was significantly decreased compared with the former three mass concentration. Absorption of ferulic acid in herbal extract was significantly higher than monomer; compared with the extract group, its absorption in probenecid group was significantly increased. The K of ligustilide in the duodenum was 3.58 ×10 -3 s-1, the order of absorption was ileum 〉 duodenum 〉 jejunum 〉 colon. The absorption of ligustilide decreased with increasing of mass concentration of herbal extract and significantly increased in groups containing verapamil and probenecid by comparing with the extract group, and the absorption of probenecid group was better than verapamil group. Conclusion： The absorption way of ferulic acid may be facilitated diffusion, existing carrier to participate in, ferulic acid is the substrate for MRP. Ligustilide mainly relies on the carrier of active transport, it may be substrates of P-gp and MRP, and it is greatly influenced by MRP.