药物转运体在银杏内酯和白果内酯药代动力学与肾脏排泄中的作用研究

发布时间：2021-01-13 21:48

　　银杏（Ginkgo biloba L.）是一种植物药,数世纪以来,因其药用特性在国际上备受关注,银杏叶制剂已被证明可用于临床治疗。因此,在过去几年中,银杏及其它植物药作为膳食补充剂的使用量急剧增加,银杏叶的市场规模逐年增长,这使得银杏叶成为美国和欧洲最畅销的膳食补充剂之一。同时,植物药使用量的激增,也引起了人们对此类制剂的质量、安全性和有效性的关注。据报道,银杏叶提取物中含有60多种具有生物活性的物质。作为主要活性成分的萜烯内酯占总生物活性成分的5～7%,可用于临床治疗,并且其药理活性与黄烷醇苷的协同作用有关,黄烷醇苷占总银杏叶提取物中生物活性成分的22～27%。银杏叶提取物（Ginkgo biloba Extract,GBE）的药理活性成分包括银杏内酯A、B、C和银杏内酯。萜烯内酯已被用于保护心脑血管和神经退行性疾病,如老年痴呆症和阿尔茨海默病。它是一种强效的抗氧化剂,能拮抗血小板活化因子（PAF）。据报道,银杏内酯对其他病症也有治疗效果,包括缺血性脑损伤,缺血后神经元损伤和炎症。近年来,在不同的细胞和动物模型中发现银杏叶提取物的抗癌作用与其抗氧化、抗血管生成和基因调控活性有关。然而... 

【文章来源】：浙江大学浙江省 211工程院校 985工程院校 教育部直属院校

【文章页数】：163 页

【学位级别】：博士

【文章目录】：
ACKNOWLEDGEMENTS
ABSTRACT
中文摘要
List of abbreviations
CHAPTER 1 Introduction
    1.1 Overview on Ginkgo biloba
    1.2 Chemistry of ginkgo biloba
    1.3 Pharmacology of ginkgolides and bilobalide
    1.4 Pharmacokinetics of ginkgolides and bilobalide
    1.5 Side effects and toxicity
    1.6 Transport and Interactions of terpene lactones with drug transporters
    1.7 The models for drug permeability study
        1.7.1 In vitro model
        1.7.2 In silico model
        1.7.3 In situ model
        1.7.4 In vivo model
    1.8 Aim and objectives
CHAPTER 2 Development and Validation of UPLC-MS/MS Method for the Determination ofGinkgolides and Bilobalide in Biosamples
    2.1. Introduction
    2.2 Material and methods
        2.2.1 Chemicals and reagents
        2.2.2 UPLC-MS/MS conditions and method
        2.2.3 Preparation of standard and QC samples
        2.2.4 Method validation
    2.3 Results and discussion
        2.3.1. Optimizing UPLC-MS/MS conditions and extraction procedure
        2.3.2 Selectivity
        2.3.3 Linearity and LLOQ
        2.3.4 Accuracy and precision
        2.3.5 Matrix effects and recovery
        2.3.6 Samples stability
    2.4 Conclusion
CHAPTER 3 Pharmacokinetics and Tissue Distribution Study of Ginkgolides and Bilobalide
    3.1 Introduction
    3.2 Materials and Methods
        3.2.1 Materials and chemicals
        3.2.2 Pharmacokinetics study of ginkgolides and bilobalide
        3.2.3 Tissue distribution study of ginkgolides and bilobalide
        3.2.4 Comparative pharmacokinetics study of bilobalide
        3.2.5 Pharmacokinetics and statistical analysis
    3.3 Results and Discussion
        3.3.1 Pharmacokinetics study
        3.3.2 Tissue distribution study
        3.3.3 Comparative study of bilobalide in GBE and pure single bilobalide
    3.4 Conclusion
CHAPTER 4 Influence of OAT 1/3 on the Pharmacokinetics and Disposition of Ginkgolides andBilobalide
    4.1 Introduction
    4.2 Material and methods
        4.2.1 Chemicals and reagents
        4.2.2 Pharmacokinetics and tissue distribution study
        4.2.3 Excretion study
        4.2.4 Uptake transport assay
        4.2.5 Pharmacokinetics and statistical analysis
    4.3 Results and discussion
        4.3.1 Uptake transport of ginkgolides and bilobalide by OAT1/3
        4.3.2 Pharmacokinetics of ginkgolides and bilobalide and Influence of OAT 1/3
        4.3.3 Renal accumulation of ginkgolides and bilobalide
        4.3.4 Urinary recovery of ginkgolides and bilobalide
    4.4 Conclusion
CHAPTER 5 In vitro characterization of OCT2-, MATE1-and MATE2K-mediated Transport ofGinkgolides and Bilobalide
    5.1 Introduction
    5.2 Materials and Methods
        5.2.1 Chemical and Reagents
        5.2.2 Cell culture and uptake study in OCT2
        5.2.3 Uptake study of MPP
        5.2.4 Uptake of ginkgolides and bilobalide
        5.2.5 Preparation and extraction of cell lysate samples
        5.2.6 LC-MS/MS Analysis of MPP
    5.3 Results and Discussion
        5.3.1 Interactions of ginkgolides and bilobalide with OCT2
        5.3.2 Inhibitory Interactions of ginkgolides and bilobalide with MATE1 andMATE2-K
        5.3.3 Substrate identification assay
        5.3.4 Transport kinetics
    5.4 Conclusion
CHAPTER 6 Permeability of Ginkgolides and Bilobalide in HBMECs and MDR1-,BCRP-,MRP2-Overexpressing Cells
    6.1 Introduction
    6.2 Materials and Methods
        6.2.1 Materials
        6.2.2 Cell cultures
        6.2.3 Cytotoxicity test on HBMEC
        6.2.4 Determination of apparent permeability in HBMEC monolayer
        6.2.5 Integrity of the cellular monolayer
        6.2.6 mRNA Detection
        6.2.7 Interaction of ginkgolides and bilobalide with the cells overexpressing ABCefflux transporters
        6.2.8 Brain distribution of ginkgolides and bilobalide in vivo
    6.3 Results and Discussion
        6.3.1 HBMEC monolayer integrity
        6.3.2 Transport of ginkgolides and bilobalide in HBMEC model
        6.3.3 Interaction of ginkgolides and bilobalide with BBB efflux transporters
        6.3.4 Co-transport of ginkgolides and bilobalide with verapamil
        6.3.5 Rats brain distribution of ginkgolides and bilobalide
    6.4 Conclusion
CHAPTER 7 Conclusion and Future Outlook
REFERENCES
List of Publications
VITA



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