PDD1滴丸的药代动力学研究

发布时间：2018-08-26 20:14

【摘要】：伪人参皂苷元DD1(Pseudoginsengenin DD1，简称PDD1)结构为（20S，24S）-达玛-20，24-环氧-3β，12β，25-三醇，是以达玛烷型原人参二醇（Protopanaxdiol，PPD1）为原料，经侧链氧化环合而成的奥克梯隆型新化合物。课题组前期研究结果表明，PDD1合成工艺成熟、具有良好的抗心律失常作用，毒理学研究结果表明其毒性较低。在此基础上，本课题组以PDD1为原料药研制开发具有抗心律失常作用的创新药物PDD1滴丸（化药1.1类），已完成了原料药及制剂的生产工艺研究、质量研究及质量标准的制定和稳定性研究，完成了主要药效学研究以及毒理学研究。血药浓度-时间曲线(Pharmacokinetics，PK)是应用动力学原理与数学处理方法，，定量的描述药物通过各种途径进入体内的吸收(Absorption)、分布(Distribution)、代谢(Metabolism)和排泄(Excretion)过程的“量时”变化动态规律[1]，简称ADME，在创新药物研究与开发过程中具有十分重要的意义[2]。本研究首次建立了大鼠血浆、组织、排泄物中PDD1的UPLC-MS/MS定量分析方法，测定了大鼠经灌胃给予PDD1滴丸和静脉注射PDD1两种给药途径大鼠生物样品中PDD1的含量。阐明了PDD1在大鼠体内的吸收、组织分布、排泄、血浆蛋白结合率和绝对生物利用度。建立了确定大鼠体内代谢物的PDD1鉴定方法，揭示了PDD1在大鼠体内的代谢规律。本论文旨在研究PDD1在大鼠体内的药代动力学，进一步阐明其有效性，安全性，为开发以PDD1为原料的抗心律失常创新药物提供科学依据。
[Abstract]:Pseudoginsenoside DD1 (PDD1 for short) is composed of (20Sn24S) -Dama -20C20-epoxy-3- 尾 -oxy-12 尾 -triol. It is a new compound of Oktiron type, which was synthesized by side chain oxidation cyclization with Protopanaxdiol,PPD1 as the raw material of pseudo-ginsenoside saponins. The results showed that the synthetic process of PDD1 was mature and had a good antiarrhythmic effect. The toxicological results showed that its toxicity was relatively low. On the basis of this, our group has developed PDD1 dropping pills with antiarrhythmic effect by using PDD1 as the raw material, and has completed the research on the production process of the raw material and its preparation. The main pharmacodynamic and toxicological studies have been completed. The plasma concentration-time curve (Pharmacokinetics,PK) is applied to the application of kinetic principles and mathematical treatment methods. Quantificationally describing the "volume time" dynamics of (Distribution), metabolism of (Metabolism) and excretion of (Excretion) through various ways, ADME, is of great significance in the research and development of innovative drugs [2]. In this study, a UPLC-MS/MS quantitative analysis method for PDD1 in plasma, tissue and excreta of rats was established for the first time. The content of PDD1 in biological samples of rats was determined by intragastric administration of PDD1 dropping pill and intravenous injection of PDD1. The absorption, tissue distribution, excretion, plasma protein binding rate and absolute bioavailability of PDD1 in rats were elucidated. A PDD1 method for identifying metabolites in rats was established, and the metabolic law of PDD1 in rats was revealed. The purpose of this paper is to study the pharmacokinetics of PDD1 in rats, to further clarify its efficacy and safety, and to provide a scientific basis for the development of novel antiarrhythmic drugs based on PDD1.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R96

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