銀杏（Ginkgo biloba L.）是一種植物藥,數(shù)世紀以來,因其藥用特性在國際上備受關(guān)注,銀杏葉制劑已被證明可用于臨床治療。因此,在過去幾年中,銀杏及其它植物藥作為膳食補充劑的使用量急劇增加,銀杏葉的市場規(guī)模逐年增長,這使得銀杏葉成為美國和歐洲最暢銷的膳食補充劑之一。同時,植物藥使用量的激增,也引起了人們對此類制劑的質(zhì)量、安全性和有效性的關(guān)注。據(jù)報道,銀杏葉提取物中含有60多種具有生物活性的物質(zhì)。作為主要活性成分的萜烯內(nèi)酯占總生物活性成分的5～7%,可用于臨床治療,并且其藥理活性與黃烷醇苷的協(xié)同作用有關(guān),黃烷醇苷占總銀杏葉提取物中生物活性成分的22～27%。銀杏葉提取物（Ginkgo biloba Extract,GBE）的藥理活性成分包括銀杏內(nèi)酯A、B、C和銀杏內(nèi)酯。萜烯內(nèi)酯已被用于保護心腦血管和神經(jīng)退行性疾病,如老年癡呆癥和阿爾茨海默病。它是一種強效的抗氧化劑,能拮抗血小板活化因子（PAF）。據(jù)報道,銀杏內(nèi)酯對其他病癥也有治療效果,包括缺血性腦損傷,缺血后神經(jīng)元損傷和炎癥。近年來,在不同的細胞和動物模型中發(fā)現(xiàn)銀杏葉提取物的抗癌作用與其抗氧化、抗血管生成和基因調(diào)控活性有關(guān)。然而... 

【文章來源】：浙江大學(xué)浙江省 211工程院校 985工程院校 教育部直屬院校

【文章頁數(shù)】：163 頁

【學(xué)位級別】：博士

【文章目錄】：
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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