| Summary: | 碩士 === 中國醫藥大學 === 營養學系碩士班 === 101 === Andrographolide (AND) is the primary bioactive component of Andrographis paniculata. This lactone diterpenoid has been proved to own diversified biological activities including anti-inflammation, anti-carcinogenesis, hypoglycemia, and hepatoprotection. This study, focusing on the pharmacokinetics and metabolism of AND, is organized as the following three parts. First of all, animal experiment is conducted to investigate the pharmacokinetics and the metabolic pathway of AND in 7-week-old Sprague-Dawley rats. Bile duct/jugular vein cannulated rats (n=4 of each group) were intragastrically given a single dose of 10mg/kg AND, 50 mg/kg AND and 940 mg/kg APE (Andrographis paniculata eathanolic extract), and blood samples were drawn over a 12-h time period. After rats are treated with a single dose of 50 mg/kg AND and 940 mg/kg APE (with 50 mg/kg AND equivalent), respectively, results show that: (1) the maximum plasma AND and APE concentrations (Cmax) are 0.35 ± 0.05 μg/ml and 0.86 ± 0.31 μg/ml, respectively, (2) the elapsed time of maximum plasma AND and APE concentrations (Tmax) are 0.50 ± 0.43 h and 0.35 ± 0.44 h, respectively, (3) the area under curve (AUC) of plasma AND and APE concentrations are 0.50 ± 0.27 h‧μg/ml and 2.17 ± 0.59 h‧μg/ml, respectively, and (4) the mean retention time (MRT) are 1.24 ± 0.64 h and 3.40 ± 0.54 h, respectively. Second, the products of incubating AND with microsomes are analyzed. Six metabolites of AND are identified by LC/MC by incubating AND with microsomes isolated from rat liver for one hour. Third, the modulatory effects of AND on the Phase I and Phase II drug-metabolizing enzymes as well as Phase III membrane transport protein in primary rat hepatocytes are evaluated. After treating rat hepatocytes with 0-20 μM AND for 24 h, the result shows that AND increases CYP 1A1/2, 2C6, 2D1, 3A2 protein and RNA expression, and transport protein OATP1B1, OATP2B1, P-gp, MRP2, and MRP3 protein expression, whereas AND inhibits CYP 2E1, 3A1, UDP-glucuronyl transferase 1A1 (UGT1A1) protein and RNA expression. EMSA further confirms that AND can increase aryl hydrocarbon receptor (AhR) and dioxin response element (DRE) as well as the binding activities of pregnane X receptor (PXR) and direct repeat separated by 4 nucleotides (DR4). From the above results, it is concluded that: (1) AND can be rapidly absorbed and metabolized by the gastrointestinal tract with 2.4% oral bioavailability, (2) there are at least 6 metabolites of AND in liver microsome, and (3) AND can increase the transcription of drug-metabolizing enzyme systems through activating AhR and PXR.
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