Impact of Cremophor-EL and Polysorbate-80 on Digoxin Permeability across Rat Jejunum: Delineation of Thermodynamic and Transporter Related Events Using the Reciprocal Permeability Approach

The effect of Cremophor-EL (Cr-EL) and polysorbate-80 (PS-80) on the transepithelial permeability of digoxin (DIG) has been evaluated using the reciprocal permeability approach to delineate thermodynamic and transporter related events. Permeability data were corrected for solubilization using the micellar association constant (Ka) obtained from Papp data generated in the presence of the nonspecific ATPase inhibitor sodium orthovanadate. In the presence of mucosal Cr-EL, a concentration dependent decrease in serosal-mucosal (S-M) and increase in M-S transport was observed. Whilst serosal Cr-EL resulted in a reduction in S-M DIG transport, no impact on M-S transport was apparent. For PS-80, the presence of either serosal or mucosal surfactant led to a decrease in secretory (S-M) DIG transport, however no effect on absorptive transport was evident. The data confirm the potential P-gp inhibitory effects of Cr-EL, but suggest that in contrast to Cr-EL, PS-80 is not a potent inhibitor of P-gp and is incapable of increasing absorptive drug transport, at least in excised rat intestinal tissue and at the concentrations tested. The data are also consistent with the involvement of additional transporters (both apical and basolateral) in the intestinal permeability of DIG, although more definitive data is required to confirm this possibility. ©2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96:280-293, 2007