OCTN转运体介导的中药有效成分生物粘附性口服胶束的构建及作用机制

Multiple mechanisms, involving intestinal drug transporter, intestinal epithelial cell bioadhesion, the inhibitions of P-glycoprotein (P-gp) and Cytochrome P450 (CYP450), play a pivotal role in the oral absorption of Chinese herbal constituents with poor solubility. However, the synergistic effect on gastrointestinal absorption, involving the organic cation / carnitine transporter (OCTN) located at the enterocyte apical membrane, the property of intestinal bioadhesion and the inhibitions of P-gp and CYP450, was unclear. Previous studies found the oral administration of paclitexal could be improved by the bioadhesion of intestinal epithelial cell and the inhibition of P-gp. Our work will construct a novel OCTN-mediated and bioadhesive oral micelle delivery system. The new drug delivery system would possess a basic skeleton of chitosan, a hydrophobic core of stearic acid and an OCTN-targeted substrate of L-carnitine, and collaboratively load quercetin as a dual inhibitor of P-gp and CYP450, for enhancing the oral bioavailability of poorly soluble herbal constituent – paclitexal. The OCTN-mediated multiple-mechanism-synergistic effect on improving the oral bioavailability of poorly soluble herbal constituent, would throw light on the combined principle of the drug intestinal absorption, and provide a new idea for establishing the drug delivery system loading the herbal constituents with synergistic function.

转运体介导、生物粘附性、P-gp抑制与CYP450抑制等在改善难溶性中药成分口服吸收中起关键作用，但位于胃肠道顶侧细胞膜的有机阳离子/左旋肉碱转运体(OCTN)介导的难溶性中药成分口服吸收及与生物粘附性、P-gp抑制、CYP450抑制的协同促吸收机制尚不清楚，前期研究发现生物粘附性与P-gp抑制能有效地促进紫杉醇的口服吸收，因此提出以紫杉醇为模型药物，构建了一种OCTN转运体介导的新型生物粘附型口服胶束给药系统。本项目拟采用生物黏附性材料壳聚糖为基本骨架，以硬脂酸修饰构建胶束疏水性内核，以左旋肉碱配体介导靶向OCTN转运体，并协同包载具有P-gp和CYP450双重抑制作用的槲皮素协同促进紫杉醇的口服吸收，探索OCTN转运体介导的多机制协同解决难溶性中药成分的口服生物利用度问题，阐明多重协同促进中药有效成分吸收的重要意义，为具有协同作用的中药有效成分联合载药的新型递药系统构建提供新的思路。

加强难溶性中药成分口服吸收是药剂学的研究热点之一。本课题基于位于胃肠道顶侧细胞膜的有机阳离子/左旋肉碱转运体(OCTN)介导、生物粘附性、P-gp抑制、CYP450抑制的协同作用，构建了一种壳聚糖聚合物纳米胶束，促进紫杉醇的口服吸收。一系列的理化性质、药动学、细胞机制研究显示，协载槲皮素的LC修饰的CS-SA@PTX胶束临界胶束浓度低(16.89 µg/ml)、粒径小(148.3±1.7 nm)、形态规整、载药量高(7.05 %)、且性能优良，具有上述促吸收协同作用，口服生物利用度达到168.8 %。该新型给药系统阐明了多重协同促进中药有效成分吸收的重要意义，并为促进难溶性药物的口服吸收提供有价值的参考。