基于栀子苷体内代谢过程增效减毒的作用研究

The efficacy and safety of traditional Chinese medicine is an important part of the modernization of Chinese medicine. In ancient time, medical practitioners of Chinese medicine have applied many methods, such as formulas and process, to achieve efficacy enhancing and toxicity reducing. With the gradually definite material basis of Chinese medicine, artemisinin, which could be the representative of some modern drugs derived from Chinese medicine, has been applied in clinical practice.It has been showed that the metabolites of many active ingredients in traditional Chinese medicine have been developed as potential effective drugs for clinical therapy for their quick absorption, wide distribution or high activity. However, some studies have also exposed that this kind of metabolites was with relatively active structures and unable to be used widely for its poor stability in vivo, lower bioavailability or potential toxicity..In this project, genipin, the metabolite of geniposide,which is one of major effective compounds of Gardenia Jasminoides Ellis, was set as a model drug for exploration of method and mechanism of enhancing efficacy and reducing toxicity of genipin. The preparation of inclusion complex or derivatives of genipin was oriented by the results of metabolism and pharmacokinetic study. Along with the study on antitumor effect and safety evaluation, the pathway and mechanism of efficacy enhancing and toxicity reducing will be further discussed and explored..The study includes: study on metabolism and pharmacokinetics of genipin, preparation of derivatives of genipin, preparation of inclusion complex of genipin with hydroxypropyl-β-cyclodextrin, study on antitumor effects and safety evaluation of genipin and its complex or derivatives.Safe and effective model drugs with genipin will be selected,whose metabolism and pharmacokinetics will also be furthermore studied.

中药的有效性和安全性是中药现代化的重要研究内容，历代医家在临床实践中采用了配伍、炮制等多种增效减毒方法。随着中药物质基础研究的深入，表明一些中药有效成分的代谢产物吸收快、活性高，具有临床开发应用价值。然而，这类代谢产物也常因其结构活泼等原因，存在体内稳定性差、生物利用度低或有潜在的毒性等问题，迫切需要通过研究解决。.项目以中药栀子有效成分栀子苷的代谢产物栀子苷元为模型药物，制备栀子苷元包合物或衍生物，以体内外代谢和药物动力学研究为导向，并通过抗肿瘤作用与安全性评价，探索其增效减毒的途径和机制，对促进中医药理论的发展有重要的理论意义和临床应用价值。.研究内容包括：栀子苷元体内药物代谢、药动学等研究；衍生物制备；羟丙基-β-环糊精/栀子苷元包合物制备；栀子苷元及其衍生物、代谢物、包合物抗肿瘤作用及安全性评价，筛选安全有效的栀子苷元类模型药物，并对其体内代谢及增效减毒作用机制做进一步深入研究。

本项目以中药栀子有效成分栀子苷的代谢产物栀子苷元为模型药物，研究栀子苷元的体内外代谢过程。以体内外代谢和药物动力学研究为导向，结合药剂学手段，制备栀子苷元环糊精包和物，并通过抗肿瘤作用与安全性评价，探索其增效减毒的途径。. 栀子苷元药代动力学研究中，大鼠体内共检测到10种代谢物，其葡萄糖醛酸和硫酸结合物为主要代谢产物。并采用半制备液相技术制备其主要代谢物，采用核磁共振图谱确定其结构为栀子苷元-1-O-葡萄糖醛酸苷。. 栀子苷元药物动力学研究结果表明：大鼠灌服栀子苷元后，栀子苷元主要代谢物（葡萄糖醛酸结合物和硫酸结合物）以栀子苷元计体内的药-时过程均符合一室模型。灌胃后2 min后即可在血浆中检测到栀子苷元硫酸和葡萄糖醛酸结合物，且5-10 min左右血浆中栀子苷元结合物的浓度即达到最大峰值。栀子苷元葡萄糖醛酸结合物占总结合物含量的百分比为62.8%-66.6%。大鼠静脉注射栀子苷元后，其体内过程与灌服给药相似，栀子苷元葡萄糖醛酸结合物占总结合物含量的百分比为65.9%。. 栀子苷元/羟丙基-β-环糊精包合物的最佳包合条件：包合时间32h、GNP和羟丙基-β-CD-环糊精摩尔比1:1、搅拌温度30℃、包合溶剂为水。包合物中栀子苷元的包合率为90.3％，含量为130mg/g。栀子苷元经羟丙基-β-环糊精制备成包合物后，其LD50增加了99.1%，安全性得到了一定的提高。大鼠灌服栀子苷元/羟丙基-β-环糊精包合物后，栀子苷元体内达峰时间为30分钟，最大血药浓度提高了5.3%，AUC(0-∞)提高了20.6%，体内滞留时间延长了34.7%。. 栀子苷元及其衍生物、包合物对人胰腺癌肿瘤细胞Panc-1增殖的抑制作用中，栀子苷元及其包合物的抑制作用较好。其抗肿瘤作用与栀子苷元结构上1-OH相关，主要通过抑制UCP2的活性、调节细胞膜电位、增加活性氧等机制来诱导细胞凋亡。体内抑瘤实验表明栀子苷元及其包合物对人胰腺癌均有一定的抑瘤作用，且栀子苷元包合物抑瘤作用优于栀子苷元。 . 本课题研究提示栀子苷元作为潜在药物，应注重对1-OH的保护，且可通过环糊精包合等技术达到增效减毒的目的。