published_or_final_version / Pharmacology and Pharmacy / Master / Master of Philosophy

The goal of this dissertation is to investigate the interaction between cimetidine and dietary flavonoids using the Caco-2 cell transport model. It has been shown that flavonoids can change the bioavailability of pharmaceuticals, either by inhibiting metabolizing enzymes or inhibiting the drug efflux transporters. However, the effect of dietary flavonoids in the absorption of cimetidine has not been investigated. Therefore, the hypothesis of this study is that the absorption of cimetidine is mediated by a drug efflux pump, P-glycoprotein, of which dietary flavonoids can enhance the permeability of cimetidine by reducing P-glycoprotein function. The increase in permeability of cimetidine can increase the bioavailability of cimetidine. To test the hypothesis, three objectives were proposed. The first objective was to validate the Caco-2 transport model in our laboratory. The validation was performed by measuring the electrical resistance ofthe monolayer and determining the transport of paracellular marker. Also P-glycoprotein function was determined using rhodamine 123. The second objective was to describe the transport characteristics of cimetidine in the Caco-2 cell monolayers. The permeability of cimetidine was determined at different pH environments. When the permeability of cimetidine from apical to basolateral and basolateral to apical was compared, there appeared to be an effiux mechanism involved transport of cimetidine. The permeability of cimetidine in the presence of verapamil, a P-glycoprotein competitive inhibitor, suggested that P-glycoprotein was involved in the effiux. The third objective was to study the effect of dietary flavonoids on the permeability of cimetidine in the Caco-2 cell model. In the present study, four different flavonoids, quercetin, genistein, naringenin, and xanthohumol were selected. When co-treated with flavonoid aglycones, the permeability ofcimetidine was significantly reduced in the basolateral to apical direction. However, only genistin, a glycoside of genistein, significantly reduced the efflux of cimetidine. The present studies demonstrate that some dietary flavonoids, especially aglycones, can significantly reduce the effiux of cimetidine in the Caco-2 cell monolayers. Therefore, the fiavonoids consumed in a normal diet have the potential to enhance the bioavailability of cimetidine and possibly other P-glycoprotein substrates by altering their permeability. / Graduation date: 2004

Poon, Ching Ho. / "October 2010." / Thesis (M.Phil.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 95-102). / Abstracts in English and Chinese. / ACKNOWLEDGEMENTS --- p.3 / TABLE OF CONTENTS --- p.4 / ABSTRACT --- p.6 / 摘要 --- p.8 / ABBREVIATIONS --- p.10 / LIST OF FIGURES --- p.11 / Chapter CHAPTER 1 --- GENERAL INTRODUCTION --- p.14 / Chapter CHAPTER 2 --- MATERIALS AND METHODS --- p.26 / Chemicals and materials --- p.26 / Mammalian cell culture --- p.27 / Reporter gene assay --- p.28 / Semi-quantitative real-time PCR --- p.30 / RNA degradation assay --- p.31 / Western Blotting --- p.32 / Electrophoretic mobility shift assay (EMSA) --- p.34 / EROD assay in intact cells --- p.35 / Statistical Analysis --- p.35 / Chapter CHAPTER 3 --- Two citrus bioflavonoids suppress DMBA-induced CYP1 gene expression and activity via antagonizing AhR transactivation activity --- p.36 / Chapter CHAPTER 4 --- Modulation of AhR-mediated CYP1 enzymes transcription by licorice flavonoids isoliquiritigenin --- p.60 / Chapter CHAPTER 5 --- Protein kinase signaling pathways are not involved in the modulation of AhR transactivation activity by flavonoids --- p.81 / Chapter CHAPTER 6 --- SUMMARY --- p.94 / BIBLIOGRAPHY --- p.97

published_or_final_version / Biological Sciences / Master / Master of Philosophy