Transfer of metformin across monolayers of human intestinal Caco-2 cells and across rat intestine

Intestinal absorption of the antihyperglycaemic agent metformin (dimethylbiguanide) was examined in vivo in rats, and using cultured monolayers of Caco-2 human intestinal epithelial cells. After intrajejunal administration of metformin (50 mg/kg) to overnight fasted rats there was a rapid (within 1 min) appearance of the drug in the plasma, and there were consistently higher concentrations of metformin in the hepatic portal vein than the inferior vena cava during the period of absorption. The transfer of metformin across Caco-2 monolayers was concentration dependent, non-saturable and non-polar. Transfer was linear for > 1 h, and theapparent permeability coefficient (P-app) was 5.5 x 10(-6) cm/s at pH 7.4. Approximately 19% of a 1 mM metformin solution was transferred from the apical to the basolateral chamber in 1 h. The P-app was decreased by 50% when the pH was decreased from 7.4 to 5.5. Metformin was not transported by the imino transport system. The results provide evidence that transepithelial transfer of metformin in the intestine is at least partly by passive permeation, possibly involving a paracellular route. Metformin drains from the intestine via the hepatic portal vein.