Efflux, generally

The second general mechanism to cause resistance to antibacterial agents is to prevent the drug from reaching its target site. This is either achieved by altered rates of entry (reduced uptake) or by the active removal of the dtug (active efflux) [4]. 

The use of Caco-2 cell monolayers has gained in popularity as an in vivo human absorption surrogate moreover, the monolayers are generally accepted as a primary absorption screening tool by several pharmaceutical companies [10]. However, Caco-2 cell permeability measurements exhibit certain limitations due to the mechanisms involved. Both passive and active pathways exist active transport tends to increase the absorption across the cells and, since Caco-2 cells overexpress the P-glycoprotein (P-gp) efflux pump, the absorption of some compounds across these cells may be underestimated. 

A variety of in vitro assays are available to identify compounds as substrates and inhibitors of P-gp. These assays, which have been reviewed elsewhere in great detail [20-24], can be classified into three general categories (1) transport, (2) accumulation/ efflux and (3) ATPase activity [20-28]. It is important to note that these in vitro model systems can be adapted for measuring the interaction of dmgs with other important drug transporter systems [22]. 

This permeability barrier shows selectivity in that small hydrophobic molecules can partition into and diffuse across the lipid bilayer of the cell membrane, whereas small hydrophilic molecules can only diffuse between cells (i.e., through the intercellular junctions). In addition, the presence of uptake and efflux transporters complicates our ability to predict intestinal permeability based on physicochemical properties alone because transporters may increase or decrease absorptive flux. The complexity of the permeability process makes it difficult to elucidate permeability pathways in complex biological model systems such as animals and tissues. For this reason, cultured cells in general, and Caco-2 cells in particular, have been used extensively to investigate the role of specific permeability pathways in drug absorption. 

---