Thesis (M.S.)--University of North Carolina at Greensboro, 2006. / Title from PDF title page screen. Advisor: Gregory Raner; submitted to the Dept. of Chemistry. Includes bibliographical references (p. 68-70).

Thesis (Ph. D.)--University of Rhode Island, 2005. / Typescript. Includes bibliographical references (leaves 129-140).

Wang, Xiaoan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 145-166). / Abstracts in English and Chinese. / Table of Contents --- p.I / Acknowledgements --- p.VI / Publications --- p.VII / Abstract (in English) --- p.VIII / Abstract (in Chinese) --- p.X / List of Figures --- p.XII / List of Tables --- p.XVI / List of Abbreviations --- p.XVII / Chapter Chapter One. --- Introduction --- p.1 / Chapter 1.1 --- Overview of oseltamivir --- p.1 / Chapter 1.1.1 --- General description of oseltamivir --- p.1 / Chapter 1.1.2 --- Pharmacological activities of oseltamivir --- p.3 / Chapter 1.1.3 --- Pharmacokinetics of oseltamivir --- p.3 / Chapter 1.1.3.1 --- Absorption of oseltamivir --- p.4 / Chapter 1.1.3.2 --- Distribution of oseltamivir --- p.5 / Chapter 1.1.3.3 --- Metabolism of oseltamivir --- p.6 / Chapter 1.1.3.4 --- Elimination of oseltamivir --- p.8 / Chapter 1.1.4 --- Side effects and toxicities of oseltamivir --- p.9 / Chapter 1.2 --- Overview of Chinese medicine formulae CMF1 (Yinqiaosan and Sangjuyin) --- p.9 / Chapter 1.2.1 --- Background and clinical use of CMF1 --- p.9 / Chapter 1.2.2 --- Quality control of CMF1 by manufacturer --- p.11 / Chapter 1.2.3 --- Major active components of CMF1 --- p.12 / Chapter 1.3 --- Previous studies on herb-drug interactions between O and CMF1 --- p.18 / Chapter 1.4 --- Rationale of the current study --- p.19 / Chapter 1.5 --- objectives --- p.19 / Chapter Chapter Two. --- Identification and quantification of major marker compounds in Yinqiaosan and Sangiuyin products --- p.20 / Chapter 2.1 --- Introduction --- p.20 / Chapter 2.2 --- Materials and methods --- p.23 / Chapter 2.2.1 --- Chemicals --- p.23 / Chapter 2.2.2 --- Instruments --- p.24 / Chapter 2.2.3 --- Chromatographic conditions --- p.24 / Chapter 2.2.4 --- Preparation of standard solutions --- p.25 / Chapter 2.2.5 --- Calibration curves --- p.26 / Chapter 2.2.6 --- Validation of the assay method --- p.26 / Chapter 2.2.7 --- Sample preparations for Yinqiaosan and Sangjuyin products --- p.27 / Chapter 2.2.7.1 --- Sample extraction from Yinqiaosan or Sangjuyin granules --- p.27 / Chapter 2.2.7.2 --- Sample extraction from Yinqiaosan or Sangjuyin tablets --- p.27 / Chapter 2.2.7.3 --- Sample extraction recoveries --- p.27 / Chapter 2.3 --- Results and discussions --- p.28 / Chapter 2.3.1 --- Chromatography --- p.28 / Chapter 2.3.2 --- Linearity and sensitivity --- p.33 / Chapter 2.3.3 --- Accuracy and precision --- p.33 / Chapter 2.3.4 --- Stability --- p.36 / Chapter 2.3.5 --- Contents of identified active components in commercial available Yinqiaosan or Sangjuyin products and CMF1 --- p.36 / Chapter 2.3.6 --- Sample extraction recovery --- p.40 / Chapter 2.4 --- Conclusion --- p.43 / Chapter Chapter Three. --- Effect of CMF1/CMF1 components on the metabolism of oseltamivir and related mechanistic studies --- p.44 / Chapter 3.1 --- Introduction --- p.44 / Chapter 3.2 --- Materials and methods --- p.47 / Chapter 3.2.1 --- Materials --- p.47 / Chapter 3.2.2 --- "Verification of metabolism of O in rat GI tract, plasma and liver microsome" --- p.48 / Chapter 3.2.3 --- Inhibition of metabolism of O by CMFl/CMFl components --- p.49 / Chapter 3.2.3.1 --- In vitro inhibition of metabolism of O in rat plasma --- p.49 / Chapter 3.2.3.2 --- In vitro inhibition of metabolism of O in rat liver microsome (RLM) --- p.49 / Chapter 3.2.4 --- Mechanistic study of enzyme inhibition of O in recombinant human Carboxylesterase 1 (hCE 1) --- p.50 / Chapter 3.2.5 --- Sample preparation and LC/MS/MS analysis --- p.50 / Chapter 3.2.6 --- Data analyses --- p.52 / Chapter 3.3 --- Results --- p.53 / Chapter 3.3.1 --- "Verification of metabolism of O in rat GI tract, plasma and liver microsome" --- p.53 / Chapter 3.3.2 --- Inhibition of metabolism of O by CMF1/CMF1 components --- p.53 / Chapter 3.3.2.1 --- Enzyme inhibition of metabolism of O by CMFl/CMF1 components in rat plasma --- p.53 / Chapter 3.3.2.2 --- Enzyme inhibition of metabolism of O by CMF1/CMF1 components in rat liver microsome (RLM) --- p.58 / Chapter 3.3.2.3 --- Selection of potent enzyme inhibitor from CMF1 --- p.60 / Chapter 3.3.4. --- Mechanistic study of enzyme inhibition of O in recombinant human Carboxylesterase 1 (hCE 1) --- p.61 / Chapter 3.4 --- Discussions --- p.63 / Chapter 3.5 --- Conclusion --- p.74 / Chapter Chapter Four. --- Effect of CMFl/CMFl components on the absorption of oseltamivir and related mechanistic studies --- p.75 / Chapter 4.1 --- Introduction --- p.75 / Chapter 4.2 --- Materials and methods --- p.79 / Chapter 4.2.1 --- Materials --- p.79 / Chapter 4.2.2 --- PAMPA permeation model --- p.80 / Chapter 4.2.2.1 --- Permeation of O and OC in PAMPA --- p.80 / Chapter 4.2.2.2 --- Sample preparation and LC/MS/MS analysis --- p.81 / Chapter 4.2.2.3 --- Data analysis --- p.81 / Chapter 4.2.3 --- Absorption of O in presence of CMF/CMFl components in Caco-2 and MDCK cell monolayer models --- p.82 / Chapter 4.2.3.1 --- Cell culture --- p.82 / Chapter 4.2.3.2 --- Preparation of loading solutions to the cell models --- p.83 / Chapter 4.2.3.3 --- Stability of O in transport buffer --- p.84 / Chapter 4.2.3.4 --- Cytotoxicity tests of O and CMFl/CMFl components --- p.84 / Chapter 4.2.3.5 --- Transport study in Caco-2 and MDCK monolayer model --- p.85 / Chapter 4.2.3.6 --- Sample preparation and LC/MS/MS analysis --- p.86 / Chapter 4.2.3.7 --- Data analysis --- p.87 / Chapter 4.2.4 --- Absorption of O in presence of CMF 1 in rat in situ single pass intestinal perfusion model --- p.88 / Chapter 4.2.4.1 --- Preparation of perfusion solutions --- p.88 / Chapter 4.2.4.2 --- Stabilities of O and arctigenin in perfusate --- p.88 / Chapter 4.2.4.3 --- Rat in situ single pass intestinal perfusion of O in presence and absence of CMFl and relevant inhibitors --- p.89 / Chapter 4.2.4.4 --- Sample preparation and LC/MS/MS analysis --- p.90 / Chapter 4.2.4.5 --- Data analysis --- p.90 / Chapter 4.3 --- Resul ts --- p.91 / Chapter 4.3.1 --- Permeation of O and OC in PAMPA --- p.91 / Chapter 4.3.2 --- Absorption of O in presence of CMF/CMF1 components in Caco-2 and MDCK cell monolayer models --- p.92 / Chapter 4.3.2.1 --- Stabilities of O in transport buffer --- p.92 / Chapter 4.3.2.2 --- Cytotoxicity tests of O and CMF1/CMF1 components in transport buffer --- p.93 / Chapter 4.3.2.3 --- Proof of O as a substrate of P-gp by Caco-2 cell model --- p.95 / Chapter 4.3.2.4 --- Effect of CMF 1 on the absorption transport of o in Caco-2 cell mode --- p.98 / Chapter 4.3.2.5 --- Effect of CMF1 components on the absorption transport of o in Caco-2 cell model --- p.102 / Chapter 4.3.2.6 --- Effect of arctigenin on bi-directional transport of o in Caco- 2 cell model --- p.106 / Chapter 4.3.2.7 --- Proof of O as a substrate of P-gp by MDCK transfected cell lines --- p.108 / Chapter 4.3.2.8 --- Bi-directional transport of O in MDCK-MDR1 cell model --- p.111 / Chapter 4.3.2.9 --- Effect of CMF 1 on the absorption transport of O in MDCK-MDR1 cell model --- p.112 / Chapter 4.3.3 --- Absorption of O in presence of CMF1 in rat in situ single pass intestinal perfusion model --- p.113 / Chapter 4.3.3.1 --- Stabilities of O and arctigenin in the perfusion buffer --- p.113 / Chapter 4.3.3.2 --- Intestinal absorption of O in presence and absence of CMF1 in rat in situ intestinal perfusion model --- p.114 / Chapter 4.4 --- Discussions --- p.116 / Chapter 4.5 --- Conclusion --- p.124 / Chapter Chapter Five. --- Preliminary evaluation of antiviral activity of CMFl/CMFl components --- p.125 / Chapter 5.1 --- Introduction --- p.125 / Chapter 5.2 --- Materials and methods --- p.128 / Chapter 5.2.1 --- Materials and animals --- p.128 / Chapter 5.2.2 --- Animal treatment --- p.129 / Chapter 5.2.3 --- Plasma sample collection and preparation --- p.130 / Chapter 5.2.4 --- Evaluation of antiviral activities of CMFl/ CMFl components --- p.130 / Chapter 5.2.4.1 --- Plaque reduction assay --- p.131 / Chapter 5.2.4.2 --- Optimization of plasma sample dilution ratio --- p.131 / Chapter 5.2.5 --- Data analyses --- p.133 / Chapter 5.3 --- Results and discussions --- p.135 / Chapter 5.3.1 --- Ex vivo evaluation of antiviral activity of CMF1 --- p.135 / Chapter 5.3.2 --- In vitro evaluation of antiviral activity of CMF1 major marker compounds --- p.139 / Chapter 5.4 --- Conclusion --- p.141 / Chapter Chapter Six. --- Overall conclusion --- p.142 / References --- p.145

In Africa, use of medicinal plants for the treatment of diabetes is very common. However, efficacy on co-administering of medicinal plants with therapeutic drugs hasn't been fully determined, especially for African medicinal plants. The current study focused on assessing the in vitro modulation effects of three popular African medicinal plants, namely: Aloe ferox, Sutherlandia frutescens and Prunus africana (including five commercial preparations containing these medicinal plants) on two of the most important anti-diabetic drug metabolising enzymes, Cytochrome P450 (CYP450) 2C9 and CYP3A4 and a key drug efflux transporter, P-glycoprotein (P-gp). Vivid® microsome-based screening kits were used to assess inhibitory potency of plants preparations on CYP2C9 and CYP3A4 enzymes activities. The study showed that P. africana was a more potent inhibitor of CYP2C9 and CYP3A4 activity than the corresponding positive controls Ginkgo biloba and St. John's wort, which are known to cause clinically significant drug-herb interactions. S. frutescens leaf extract demonstrated potent to moderate inhibition on both the tested CYP activities, while its commercial products (Promune® and Probetix®) possessed moderate to mild inhibitory effects on the activities of both CYPs. Potent inhibitory effect on CYP2C9 and CYP3A4 was seen with Aloe Ferox®. Prosit® and Aloes powder® showed potent to moderate inhibition on CYP2C9 activity and moderate to mild inhibition on CYP3A4 activity. In addition to CYP450 activity, the present study also investigated the effects of the selected medicinal plant products on the activity of the main drug efflux protein, P-gp. A screening assay was specifically developed to assess the potential for herbal remedies to interact with P-gp mediated drug absorption. The assay is based on the principle of the reversal of drug resistance in modified Caco-2 cells specifically altered to express high iv efflux protein activity. These cells display a multidrug resistance phenotype and the addition of a plant extract containing a P-gp inhibitor or substrate will inhibit or compete with any cytotoxic drug and consequently reverse the drug resistance. The suitability of the assay was confirmed using a known P-gp inhibitor. The study observed that the anti-proliferation effect of vinblastine was significantly enhanced in vinblastine-resistant Caco-2 cells, which have high P-gp expression, when they were exposed to the selected African herbal preparations. This observation indicates that the studied plant preparations may alter P-gp functionality and therefore lead to interference with the absorption of co-administered drugs. The outcomes of this study provide useful information on whether there are any potential drug-herb interactions between the commonly used African medicinal plants and oral anti-diabetic drugs, at the level of CYP and P-gp drug metabolism and could contribute to better therapeutic management of Type II diabetics. However these predicted interactions will need to be verified in a clinical setting.