基于代谢组学和多组分PK-PD模型的中药脐部给药生物药剂学特征研究

As a traditional therapeutic method, umbilical compress therapy (UCT) is widely used in Traditional Chinese Medicine clinics. However, the mechanism of action of UCT remains unclear; in particular, the mechanism of absorption of drugs through the umbilical region and the intracorporeal processes are unknown. According to the results of our previous studies, the efficacy and delivery of drugs applied at the umbilicus were higher than for drugs applied on the side region. In this project, the biopharmaceutical characteristics of a drug applied on the umbilicus will be investigated, including the ADME (absorption, distribution, metabolism, and excretion), as well as the correlation between the intracorporeal processes and the pharmacodynamic effects. Xiaozhang cataplasm is selected as the model drug, and its ADME when administered via UCT will be explored. In addition, metabonomics analysis will be conducted to search for biomarkers of effect on cirrhotic ascites, and pharmacokinetics/pharmacodynamics models will be established for both umbilicus and side region application of the drug, then the results will be compared by employing artificial neural network (ANN) analysis. Accordingly, the scientific hypothesis will be verified: “An exceptional absorption channel exists in the umbilical zone, and after topical application of drug in this zone, the drug molecules that permeate through the umbilical skin into systemic circulation exhibit unique ADME characteristics, which can be correlated with the regulation of particular metabolites in the body .”. Furthermore, the research findings may be conducive to uncovering the special action mechanism of UCT.

脐部给药是中医药学独具特色的给药方式，临床应用广泛，疗效确凿。但是，目前对药物经脐部给药后的作用机制尚不明确。申请人前期研究发现，脐部给药可增加药物的经皮吸收，增强药效。在此基础上，本项目以消胀贴膏为模型药物，深入考察药物的体内过程与吸收机制，并采用代谢组学方法，分析脐部给药治疗肝硬化腹水作用的生物标志物，以人工神经网络分析多组分PK-PD模型，阐释脐部给药的生物药剂学特征，从而验证“药物在脐部具有特殊的吸收转运途径，脐部给药表现出特殊的体内过程，这与生物体内某些代谢产物的特异性调控具有关联性”的科学假说，探讨脐部给药的作用机制，丰富脐部给药的科学内涵。

脐部给药是中医学独特的治疗方法，临床应用广泛，但其作用机制尚不明确。本研究以消胀贴膏为模型药物，运用代谢组学技术，研究、探讨了药物经脐部给药的生物药剂学特征和治疗肝硬化腹水的作用机制。主要内容包括 ：（1）采用UPLC/ESI-QTOF-MS/MS与GC-MS技术建立了消胀贴膏甲醇提取物与挥发油的指纹图谱，明确了消胀贴膏所含的化学成分。（2）采用苯巴比妥联合CCl4法建立了大鼠肝硬化腹水模型，利用在体微透析技术研究了局部药代动力学特征，结果表明脐部给药可显著提高有效成分在皮肤中的Cmax与AUC0-t，促进有效成分的经皮吸收。（3）研究了大鼠体内药代动力学，发现病理因素对消胀贴膏的体内药动学行为有显著影响，有效成分在肝硬化腹水大鼠血液中的Cmax与AUC0-t显著升高，同时t1/2与MRT0-t显著延长。（4）研究了消胀贴膏经脐部给药对大鼠内源性代谢物的影响，以及生物标志物的表达差异。结果表明调节氨基酸代谢紊乱是消胀贴膏治疗肝硬化腹水的重要作用机制，其中精氨酸/一氧化氮代谢通路是药物作用的关键通路，消胀贴膏可抑制小肠中iNOS与nNOS的表达，缓解精氨酸代谢异常，降低一氧化氮水平，从而增强肝硬化腹水大鼠的胃肠动力，促进腹水的消退。（5）建立了中药多组分PK-PD模型，发现消胀贴膏整合组分与药效动力学指标之间具有良好的相关性，且整合组分在脐部给药组中的Emax与EC50相对于脐旁给药组有显著的提升。（6）运用UPLC-Q/Orbitrap-MS/MS分析技术，对消胀贴膏给药前后肝硬化腹水患者血清与尿液内源性代谢轮廓的变化进行分析。验证了消胀贴膏的作用机制主要是通过调节机体氨基酸及其代谢产物的水平，改善机体神经、免疫与内分泌网络状况，从而缓解肝硬化腹水及其伴随症状。本项目所取得的研究成果对阐明中药脐部给药作用机制、丰富脐部给药的科学内涵有重要意义。