Received for publication December 20, 2007.
Revised April 29, 2008.
Accepted for publication April 30, 2008.

Mechanisms Underlying Saturable Intestinal Absorption of Metformin

Abstract

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~0.05 mM, J_max ~1.0 pmol min^-1 cm^-2, and K_{d, transport} ~10 nL min^-1 cm^-2). AP uptake data also supported the presence of saturable and nonsaturable components (K_m~0.9 mM, V_max ~330 pmol min^-1 mg protein^-1, and K_{d, uptake} ~0.04 µL min^-1 mg 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 GW918, a P-gp inhibitor. AP efflux was trans-stimulated by metformin and prototypical substrates of organic cation transporters (OCTs), 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 mM and 10 mM metformin concentrations, respectively. Kinetic modeling of cellular accumulation and transport processes fits the data and 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 of a saturable mechanism in the paracellular space and provides insight into possible mechanisms for the dose-dependence of metformin absorption in vivo.

Key words: absorption, drug absorption, drug efflux, intestinal transport, membrane barriers, organic cation transport, permeability, transporters