碩士 / 國立成功大學 / 臨床藥學研究所 / 93 / Metformin（N,N-dimethylbiguanide, MET） is an oral biguanide antihyperglycemic agent. The absorption of metformin in gastrointestinal tract is incomplete and saturable. Although metformin can be absorbed from the whole intestine, with the main absorption site in the upper intestine, the detail mechanisms for its intestinal absorption remain unclear.
The aim of this study is to investigate the intestinal transport mechanism of MET. The in vitro intestinal everted sac preparation was used to examine the transport characteristics and the apparent permeability coefficient of MET. The effects of a variety of drugs on MET transport were also assessed. The in vivo absorption and disposition kinetics of MET and its metabolite M5 were studied in rats following oral administration and in rabbits after intravenous administration, respectively, to explore the dose-linearity.
The results of in vitro studies showed that besides passive diffusion, there were Na+-dependent transporters involved in transporting MET, with the polarity of transport from mucosa side to serosa side. In the absence of proton gradient, taurodeoxycholic acid facilitated the efflux of MET from serosa side to mucosa side. Further studies with typical substrates and inhibitors of various transporters suggested that OCTN2 and GLUT2, but not OCT1, PEPT1 and SGLT1, may be involved in the intestinal transport of MET.
Following oral administration, the apparent oral clearance of MET increased with increasing dose, indicating that the absorption was saturable. The pharmacokinetics of MET and its metabolite M5 in rabbits after intravenous administration displayed nonlinearity, as shown by the disproportional increases in the AUC of both MET and M5 with increasing dose. Because MET is mainly excreted by active renal tubular secretion, the disproportionality in AUC and hence clearance of MET might be due to saturation of the secretion process.
In conclusion, the intestinal transport of MET was probably mediated by OCTN2 and GLUT2, and taurodeoxycholic acid can increase the efflux of MET. Oral absorption of MET in rats was dose-dependent. The disposition kinetics of MET and its metabolite M5 in rabbits were nonlinear. The metabolite M5 of MET can be found in rats and rabbits.
| Identifer | oai:union.ndltd.org:TW/093NCKU5522002 |
| Date | January 2005 |
| Creators | San-Ying Lee, 李珊瑩 |
| Contributors | Chen-Hsi Chou, 周辰熹 |
| Source Sets | National Digital Library of Theses and Dissertations in Taiwan |
| Language | zh-TW |
| Detected Language | English |
| Type | 學位論文 ; thesis |
| Format | 98 |
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