Mechanisms underlying saturable intestinal absorption of metformin

The purpose of the study was to elucidate mechanisms of metformin absorptive transport to explain the dose-dependent absorption observed in humans. Apical (AP) and basolateral (BL) uptake and efflux as well as AP to BL (absorptive) transport across Caco-2 cell monolayers were evaluated over a range of concentrations. Transport was concentration-dependent and consisted of saturable and nonsaturable components (K(m) similar to 0.05 mM, Jmax similar to 1.0 pmol min(-1) cm(-2), and K(d, transport) similar to 10 nl min(-1) cm(-2)). AP uptake data also revealed the presence of saturable and nonsaturable components (K(m) similar to 0.9 mM, V(max) similar to 330 pmol min(-1) mg of protein(-1), and K(d, uptake) similar to 0.04 mu l min(-1) mg of protein(-1)). BL efflux was rate- limiting to transcellular transport of metformin; AP efflux was 7-fold greater than BL efflux and was not inhibited by N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]phenyl)-9,10- dihydro-5-methoxy-9-oxo-4-acridine carboxamide GW918), a P-glycoprotein inhibitor. AP efflux was trans-stimulated by metformin and prototypical substrates of organic cation transporters, suggesting that a cation-specific bidirectional transport mechanism mediated the AP efflux of metformin. BL efflux of intracellular metformin was much less efficient in comparison with the overall transport, with BL efflux clearance accounting for similar to 7 and similar to 13% of the overall transport clearance at 0.05 and 10 mM metformin concentrations, respectively. Kinetic modeling of cellular accumulation and transport processes supports the finding that transport occurs almost exclusively via the paracellular route ( similar to 90%) and that the paracellular transport is saturable. This report provides strong evidence for a saturable mechanism in the paracellular space and provides insight into possible mechanisms for the dose dependence of metformin absorption in vivo.