TY - JOUR T1 - Mechanisms Underlying Saturable Intestinal Absorption of Metformin JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1650 LP - 1658 DO - 10.1124/dmd.107.020180 VL - 36 IS - 8 AU - William R. Proctor AU - David L. Bourdet AU - Dhiren R. Thakker Y1 - 2008/08/01 UR - http://dmd.aspetjournals.org/content/36/8/1650.abstract N2 - 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 (Km ∼ 0.05 mM, Jmax ∼ 1.0 pmol min-1 cm-2, and Kd, transport ∼ 10 nl min-1 cm-2). AP uptake data also revealed the presence of saturable and nonsaturable components (Km ∼ 0.9 mM, Vmax ∼ 330 pmol min-1 mg of protein-1, and Kd, uptake ∼ 0.04 μl 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 ∼7 and ∼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 (∼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. The American Society for Pharmacology and Experimental Therapeutics ER -