大黃蒽醌在正常及潰瘍性結腸炎大鼠的藥代動力學研究
| Autor: | 吳文進 |
|---|---|
| Jazyk: | čínština |
| Rok vydání: | 2011 |
| Předmět: | |
| Druh dokumentu: | UM_THESES |
| Popis: | Background: Ulcerative colitis is an inflammatory disease in the colonic mucosa and submucosa with an unknown etiology. Ulcerative colitis relapses easily and it is difficult to cure. Imbalance of intestinal bacteria is considered an important factor in the pathogenesis of ulcerative colitis. As a famous traditional Chinese medicine, rhubarb obtains good effect in the treatment of ulcerative colitis clinically. Anthraquinone is the most important polyphenolic compounds in Rhubarb. In vivo pharmacokinetics of Rhubarb anthraquinones in rat or human have been reported for many times. Glucuronide conjugates were believed to be the main form of anthraquinones in body. However, there are no reports on the pharmacokinetics of Rhubarb anthraquinones in the pathological state of ulcerative colitis. In present study, we aimed rats to study in vivo pharmacokinetic profiles of rhubarb anthraquinone, the changes of intestinal bacterial metabolism and intestinal bacteria, in the ulcerative colitis, compared to the normal rats, and we tried to discuss the links among them. Finally, in vitro glucuronidation of anthraquinones were researched in order to explain the in vivo pharmacokinetics of anthraquinones, and the structrue and metabolism relationship was disscussed in glucuronidation. Methods: Dextran sulfate sodium was used to induce ulcerative colitis in SD rats. In vivo pharmacokinetic characterization of anthraquinones were studied in the pathological mode. The metabolism ability towards anthraquinone glycosides was studied in the intestinal bacteria metabolism model. The changes of intestinal bacteria were investigated by real-time PCR technology. In vitro glucuronidation of anthraquinones were researched in order to explain the in vivo pharmacokinetics of anthraquinones. Results: Pharmacokinetic studies showed that glucuronide conjugates were the main form of anthraquinones in vivo. In ulcerative colitis rats, AUC and T1/2 of anthraquinones changed after hydrolysis, so did the ratio of AUC between before hydrolysis and after hydrolysis. In the intestinal bacterial metabolism experiments, the activity catalyzing anthraquinone glucosides to aglycones of intestinal bacteria was lower in the pathological mode, compared to the healthy rats. However, the more aglycones were transformed to other compounds in UC rats. As well as C.leptum, the probiotic Bifidobacterium and and Lactobacillus decreased, however, B.fragilis incrased significantly in the pathological model. When the model is done, C.coccoides and Enterobacteriaceae in UC rats almost equied to that in the healthy rats. In vitro glucuronidation studies found that rhubarb anthraquinones except rhein underwent intense glucuronidation. The elimination rate and positional preference of glucuronidation varied with substituted position and moiety. UGT 1A catalyzed glucuronidation of most anthraquinones at varied activity and positional preference. UGT 1A9 showed the highest activies at most cases. Conclusion: In ulcerative colitis rats, the decrease of Bifidobacterium and Lactobacillus, and the changes of other bacteria, resulted in lower anthraquinone aglycones exposure to the intestinal, which might be a important reason why the pharmacokinetic parameters of anthraquinone changed. Glucuronide conjugates were the main pattern of anthraquinones in vivo due to the high glucuronidation activity of anthraquinones that was confirmed. University of Macau Institute of Chinese Medical Sciences |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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