Metformin（N,N-dimethylbiguanide, MET）為一廣泛被使用的雙胍類口服降血糖藥物。MET於腸胃道吸收並不完全且吸收過程有飽和的現象。雖然整段腸子皆可吸收MET，且主要的吸收部位在腸道的上段，但是目前對於MET由腸道吸收的詳細機轉仍不清楚。
　　因此本研究目的在於利用體外翻轉腸囊（in vitro intestinal everted sac）與大鼠體內口服吸收試驗的方法探討MET於大鼠腸道運輸及體內口服吸收的情形。另外先前本實驗室已證實靜脈注射與靜脈輸注MET於大鼠體內有代謝物M5生成，然而文獻卻尚未於其他物種體內發現有代謝物M5的形成。因此本實驗亦於家兔身上靜脈注射MET以探討MET於不同物種間體內動態的差異，並觀察是否有代謝物M5的形成。
　　體外翻轉腸囊試驗的結果顯示，MET於腸道的運輸除了被動擴散之外，亦有鈉依存性的載體負責運輸，主要運輸方向為由黏膜層往漿膜層，而在無pH梯度時膽鹽會促進MET由漿膜層往黏膜層方向的運輸。進一步研究顯示OCTN2及GLUT2載體與MET在腸道的運輸有關，而有機陽離子載體（organic cation transporter，OCT）、intestinal peptide transporter 1（PEPT1）、SGLT1則與MET於腸道的運輸無關。
　　以不同口服劑量投與老鼠體內，發現隨著劑量的增加，MET的吸收有飽和的現象，且有代謝物M5的形成。靜脈注射MET於家兔體內亦發現有此代謝物形成，而且不論是MET或M5在家兔體內，當投予劑量增加時血中濃度曲線下面積均呈現非比例的增加，而清除率則有下降的情形，呈現出飽和的現象。可能是因為MET主要經由腎小管主動分泌排除，所以在高劑量之下，MET飽和了這個作用因而使得清除率下降、血中濃度曲線下面積增加。
　　由本研究之體內體外實驗結果所得到的結論為MET於大鼠腸道之穿透可能受到OCTN2、GLUT2載體的調控，且腸道內的膽鹽亦可影響其腸道運輸。MET於大鼠之口服吸收有飽和的現象，而MET在家兔體內之藥物動力學則呈現非線性的情形。此外，本研究也證實了MET在大鼠與家兔體內皆有代謝物M5的形成。

　　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.

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