A study to investigate the mechanisms of the drug interactions between danshen and warfarin.

Wu Wai Ping.Thesis (M.Phil.)--Chinese University of Hong Kong, 2004.Includes bibliographical references (leaves 163-177).Abstracts in English and Chinese.Abstract --- p.i摘要 --- p.ivAcknowledgement --- p.viTable of Contents --- p.viiAbbreviations --- p.xChapter Chapter 1 --- General introduction --- p.11Chapter 1.1 --- Introduction --- p.11Chapter 1.1.1 --- "Origin, processing and delivery form of TCM" --- p.11Chapter 1.1.2 --- Problems about the uses of TCM --- p.13Chapter 1.1.2.1 --- Quality control --- p.13Chapter 1.1.2.2 --- Efficacy --- p.14Chapter 1.1.2.3 --- Herb-drug interactions --- p.14Chapter 1.1.2.4 --- Authentication --- p.15Chapter 1.1.3 --- Commonly used Traditional Chinese Medicine --- p.15Chapter 1.2 --- Interactions between TCM and warfarin --- p.17Chapter 1.2.1 --- Danshen-warfarin interactions --- p.19Chapter 1.3 --- Danshen --- p.20Chapter 1.3.1 --- Chemical constituents --- p.20Chapter 1.3.2 --- Pharmacological effects of danshen --- p.24Chapter 1.3.2.1 --- Anti-oxidant effects --- p.24Chapter 1.3.2.2 --- Effects on liver fibrosis --- p.25Chapter 1.3.2.3 --- Effects on tumours --- p.26Chapter 1.3.2.4 --- Effects on cardiovascular system --- p.26Chapter 1.3.2.5 --- Effect on platelet aggregation --- p.27Chapter 1.4 --- Warfarin --- p.27Chapter 1.4.1 --- Pharmacology --- p.28Chapter 1.4.2 --- Pharmacokinetics --- p.30Chapter 1.4.3 --- Metabolism --- p.30Chapter 1.4.4 --- Warfarin-drug interactions --- p.32Chapter 1.4.4.1 --- Pharmacokinetic Interactions --- p.32Chapter 1.4.4.2 --- Pharmacodynamic interactions --- p.34Chapter 1.5 --- Aim of study --- p.35Chapter Chapter 2 --- Effects of danshen extract and some of its active ingredients on warfarin metabolism in rat liver microsomes --- p.36Chapter 2.1 --- Introduction --- p.36Chapter 2.2 --- Materials and methods --- p.39Chapter 2.2.1 --- Chemicals and reagents --- p.39Chapter 2.2.2 --- Animals --- p.39Chapter 2.2.3 --- Preparation of rat hepatic microsomes --- p.40Chapter 2.2.4 --- Protein assay --- p.40Chapter 2.2.5 --- Preparation of aqueous fraction and ethanolic fractions of danshen from danshen roots --- p.41Chapter 2.2.5.1 --- Aqueous extract of danshen --- p.41Chapter 2.2.5.2 --- Ethanolic extract of danshen --- p.42Chapter 2.2.6 --- Incubation condition for warfarin metabolism --- p.42Chapter 2.2.7 --- Effects of danshen extract and some of its active ingredients on warfarin metabolism in vitro --- p.43Chapter 2.2.8 --- Effects of danshen extract and some of its sctive ingredients on enzyme kinetics of warfarin metabolism in vitro --- p.44Chapter 2.2.9 --- High Pressure Liquid Chromatography (HPLC) analysis --- p.45Chapter 2.2.10 --- Calibration curves and validation of the HPLC systems --- p.48Chapter 2.2.11 --- Data analysis --- p.52Chapter 2.3 --- Results --- p.53Chapter 2.3.1 --- Effects of danshen extract on warfarin metabolism --- p.53Chapter 2.3.2 --- Effects of aqueous extract of danshen on warfarin metabolism --- p.60Chapter 2.3.3 --- Effects of ethanolic extract of danshen on warfarin metabolism --- p.62Chapter 2.3.4 --- Effects of tanshinone I on warfarin metabolism --- p.64Chapter 2.3.5 --- Effects of tanshinone IIA on warfarin metabolism --- p.70Chapter 2.3.6 --- Effects of cryptotanshinone on warfarin metabolism --- p.76Chapter 2.3.7 --- IC20 of danshen extract and its components on warfarin metabolism --- p.82Chapter 2.4 --- Discussion --- p.84Chapter Chapter 3 --- Effects of danshen extract and some of its active ingredients on warfarin metabolism in human pooled liver microsomes and the human CYP2C9 isoform --- p.89Chapter 3.1 --- Introduction --- p.89Chapter 3.2 --- Materials and methods --- p.92Chapter 3.2.1 --- Chemicals and reagents --- p.92Chapter 3.2.2 --- Incubation conditions for warfarin metabolism --- p.92Chapter 3.2.3 --- Effects of danshen extract and its components on warfarin metabolism in vitro --- p.93Chapter 3.2.4 --- High Pressure Liquid Chromatography (HPLC) analysis --- p.94Chapter 3.2.5 --- Calibration curves --- p.95Chapter 3.2.6 --- Data analysis --- p.95Chapter 3.3 --- Results --- p.96Chapter 3.3.1 --- Effects of danshen extract and its components on warfarin metabolism by using human pooled liver microsomes --- p.96Chapter 3.3.2 --- Effects of danshen extract and its components on S-warfarin metabolism by using human lymphoblast CYP2C9 isoform --- p.103Chapter 3.4 --- Discussion --- p.111Chapter Chapter 4 --- Effects of acute and subchonic pretreatment of danshen extract on the pharmacokinetics of warfarin in the rats in vivo --- p.115Chapter 4.1 --- Introduction --- p.115Chapter 4.2 --- Materials and methods --- p.118Chapter 4.2.1 --- Chemicals and reagents --- p.118Chapter 4.2.2 --- Animals Table of Contents --- p.118Chapter 4.2.3 --- Effects of acute danshen extract pretreatment on the pharmacokinetics of warfarin --- p.119Chapter 4.2.4 --- Effects of subchronic danshen extract pretreatment on the pharmacokinetics of warfarin --- p.119Chapter 4.2.5 --- Steady state warfarin study --- p.120Chapter 4.2.6 --- Sample extraction --- p.120Chapter 4.2.7 --- High Pressure Liquid Chromatography (HPLC) analysis --- p.121Chapter 4.2.8 --- Calibration curve --- p.121Chapter 4.4 --- Results --- p.123Chapter 4.3.1 --- Effects of acute danshen extract pretreatment on the pharmacokinetics of warfarin --- p.123Chapter 4.3.2 --- Effects of subchronic danshen extract pretreatment on the pharmacokinetics of warfarin --- p.128Chapter 4.3.3 --- Steady state warfarin study --- p.136Chapter 4.5 --- Discussion --- p.138Chapter Chapter 5 --- Effects of danshen extract on the absorption of warfarin by using Caco-2 cells model --- p.142Chapter 5.1 --- Introduction --- p.142Chapter 5.2 --- Materials and methods --- p.144Chapter 5.2.1 --- Materials for Caco-2 cells culture experiment --- p.144Chapter 5.2.2 --- Preparation of Caco-2 monolayer --- p.144Chapter 5.2.3 --- High Pressure Liquid Chromatography (HPLC) analysis for warfarin --- p.145Chapter 5.2.4 --- Calibration curve --- p.145Chapter 5.2.5 --- Stability test for warfarin and danshen extract --- p.145Chapter 5.2.6 --- Toxicity test of danshen extract on Caco-2 cells --- p.146Chapter 5.2.7 --- Transport study --- p.146Chapter 5.2.8 --- Data Analysis --- p.147Chapter 5.3 --- Results --- p.149Chapter 5.3.1 --- Stability of warfarin and danshen extract --- p.149Chapter 5.3.2 --- Toxicity test of danshen extract on Caco-2 cells --- p.149Chapter 5.3.3 --- Integrity of Caco-2 cells monolayer --- p.152Chapter 5.3.4 --- Transport study --- p.152Chapter 5.4 --- Discussion --- p.154Chapter Chapter 6 --- General discussion --- p.156References --- p.16