The attenuation of the driving force is most pronounced when there is an excess of the solubilizing agent relative to the amount needed to completely solubilize the drug. The effect has been demonstrated in vitro in Caco2 assays as shown in Figure 8 (data re-plotted from Nerurkar, et al., 1996 and Yu, et al., 1999). In both examples surfactant added acted as a P-gp efflux inhibitor. At low concentrations, the AP (apical) to BL (basolateral) flux increased with a corresponding decrease in the BL to AP flux. As the concentration of solubilizing agent further increased, a decrease in the AP to BL flux was observed and was attributed to the competition of the surfactant micelles for drug molecules and therefore a decrease in the chemical potential across the Caco2 membrane.
(a) Permeability of Acf(N-Mef) 2NH2 (b) Permeability of Amprenavir
% w/v Cremophore EL Vitamin E-TPGS Concentration (mg/ml)
Figure 8. Effect of solubilizing agents on permeability in Caco2 assays demonstrating P-gp efflux inhibition at low surfactant concentrations and decreased chemical potential at higher surfactant concentrations. Data re-plotted from (a) Nerurkar, et al., 1996 and (b) Yu, et al., 1999.
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