Metformin could be absorbed from the whole intestine, with the main absorption site at duodenum. This concentration-dependent permeability behavior in the duodenum indicates that metformin is transported by both passive and active carrier-mediated saturable mechanism. The P(eff) value can not be increased by co-perfusion with verapamil, indicating that absorption of metformin is not efficiently transported by P-gp in the gut wall. Furthermore metformin is neither a substrate nor an inducer of P-gp. Based on the P(eff) values obtained in the present study and using established relationships, the human fraction dose absorbed for metformin is estimated to be 74%-90% along human intestine.

No abstract

SummaryIn Escherichia coli, glnA (encoding glutamine synthetase) is transcribed from two promoters (glnAp1 and glnAp2). The glnAp1 is a s 70 -dependent promoter that is activated by the cAMP receptor protein (CRP). Under nitrogen-deficient growth conditions, glnAp1 is repressed by NtrC-phosphate. The downstream glnAp2 promoter is s 54 -dependent and is activated by NtrC-phosphate. Here, we show that glnAp2 expression is affected by different carbon sources and that the CRP-cAMP complex inhibits the glnAp2 promoter activity. Primer extension and KMnO 4 footprinting analysis indicate that the inhibitory effect is at the transcriptional level in vivo. When glnAp2 is activated by NifA, a similar inhibitory effect by CRP -cAMP is observed. Site-directed mutagenesis and deletion analysis indicate that the characterized and putative CRP-binding sites located in the upstream region of the glnAp2 promoter are not essential for the inhibitory effect. CRP -cAMP inhibits s 54 -dependent glnAp2 strongly, by 21-fold. By activating glnAp1 and downregulating glnAp2, the overall effect of CRP -cAMP on glnA expression is an approximately fourfold reduction, which correlates with the reduction of g-glutamyl transferase activities in the cells. We propose therefore that a physiological role of CRP -cAMP activation of glnAp1 is to partially compensate for CRP -cAMP downregulation of glnAp2, allowing a low but non-negligible level of expression of the important genes transcribed from it. A novel regulatory linkage between carbon and nitrogen regulons is proposed.

Fluid resuscitation with HES in the early stages of SAP can decrease the risk of intra-abdominal hypertension and reduce the use of mechanical ventilation.

No abstract