基于盐影响胶束缔合性质研究盐补骨脂-盐小茴香组成补骨脂丸增效机理

Previous studies have found that salt-processing enhanced Psoraleae Fructus efficiency through changing components dissolution and improving absorption. However, the underlying mechanism is still unclear. This project is tightly around the two major characteristics of Chinese medicine, i.e., herbal processing and compatibility, and takes "salt influences associating property of micelle, as well as the consequent dissolution characteristics of components in vitro and absorption feature in vivo" as the breakthrough point to propose the hypothesis: the enhanced treatment effects Buguzhi pill (salt-processed Psoraleae Fructus and Foeniculi Fructus) on spleen kidney yang deficiency induced diarrhoea could be attributed to the influence of salt on associating property of mixed micelles in vitro and/or in vivo, i.e., salt influences the associating property of phospholipid mixed micelles in water decoction and increases the dissolution of components in vitro; salt influences the associating property of lipids (components in herbal)-bile salt (internal) mixed micelles and improves the drug absorption in vivo. Animal models of diarrhoea, as well as metabolomics approach are employed to evaluate the enhanced treatment effects of Buguzhi pill from macro and micro perspective. Chemical composition and pharmacokinetics study are adopted to compare the differences of dissolution and absorption between Buguzhi pill and analogue Buguzhi pill, interpreting the enhancing approach. Based on micelle theory, representative fractions and components of Buguzhi pill, as well as the mixed micelles formed by them are prepared to investigate the influence of salt on associating property of mixed micelles in vitro and in vivo. This project exhibits great potential in revealing the enhancing mechanism of Buguzhi pill.

前期研究发现，补骨脂盐炙后通过改善成分溶出和吸收增效，但影响其增效关键环节尚不明晰。本项目紧密围绕中医用药的两大特色（炮制和复方配伍），以“盐影响胶束缔合性质，进而影响药物体外溶出、体内吸收行为”为切入点，提出研究假说：补骨脂丸（盐补骨脂、盐小茴香）可增效治疗脾肾阳虚所致泄泻，是通过盐影响体内和（或）外“混合胶束”缔合性质起效：在内是影响其脂类成分与体内胆酸盐混合胶束缔合性质，改善药物吸收；在外是影响其脂类混合胶束缔合性质，增加成分溶出。采用药效学及代谢组学研究方法，从宏观和微观上评价补骨脂丸较模拟补骨脂丸具有增效作用；采用成分化学和药动学研究方法，比较补骨脂丸和模拟补骨脂丸成分溶出和吸收差异，阐述其增效途径；制备补骨脂丸代表性部位或成分及其混合胶束，采用胶束研究方法，探讨食盐对其体内、体外混合胶束缔合性质的影响，揭示其关键环节。本项目开展可初步阐明盐炙药物组成补骨脂丸的增效机理。

本项目为国家自然科学基金小额资助项目，执行年限两年。本项目紧密围绕中医用药的两大特色（炮制和复方配伍），以“盐影响胶束缔合性质”为切入点，提出研究假说：补骨脂丸（盐补骨脂、盐小茴香）可增效治疗脾肾阳虚所致泄泻等，是通过盐影响体内和（或）外“混合胶束”缔合性质起效。为了验证这一假设，本项目以补骨脂丸为研究对象，在系统总结补骨脂、小茴香研究的基础上，开展了补骨脂、小茴香盐炙及配伍组成补骨脂丸增强止泻作用研究，证实补骨脂丸温肾助阳、暖脾止泻的作用优于补骨脂单用且具有盐炙增效的特点；开展了盐炙及配伍对补骨脂丸化学成分的影响，发现补骨脂丸中药物盐炙增加芦丁、异补骨脂二氢黄酮、新补骨脂异黄酮、补骨脂二氢黄酮、补骨脂宁、补骨脂二氢黄酮甲醚等体外溶出，抑制茴香醛、反式茴香脑、补骨脂素、异补骨脂素、补骨脂酚等体外溶出，进行了不同炮制方法对补骨脂脂溶性和挥发性成分的影响研究，发现炮制能够降补骨脂中所含脂溶性和挥发性成分的总含量，调整成分的相对含量和种类，产生新的成分；开展了基于代谢组学的补骨脂丸盐炙、配伍机理研究，发现盐炙和配伍通过影响补骨脂丸化学成分，调节体内关键代谢物，适度修复代谢紊乱，从而实现增强止泻的作用；运用胶束研究方法，探讨了盐对卵磷脂、脂肪酸、胆酸盐模拟混合胶束缔合性质的影响，发现无机盐能影响卵磷脂、脂肪酸体外混合胶束及卵磷脂、脂肪酸、胆酸盐体内混合胶束的性质，且对代表性成分影响不同，提示盐炙和配伍影响生物表面活性剂缔合胶束的性质可能是盐补骨脂、盐小茴香组成补骨脂丸增效的关键途径。但盐炙和配伍后对不同成分影响不同，表现改善、抑制的双向调节作用，这是否与补骨脂、小茴香盐炙后既能增效、又能缓性有关，还有待进一步研究。该研究初步阐明盐炙药物组成补骨脂丸的增效机理，对其他盐炙药物炮制机理研究有一定的借鉴意义。