Scaling of in vitro membrane permeability to predict P-glycoprotein-mediated drug absorption in vivo

In a previous study, the concentration-dependent permeability of P-glycoprotein (P-gp) substrate drugs, quinidine, verapamil, and vinblastine, in several cell monolayers with different levels of P-gp expression was analyzed kinetically to obtain fundamental parameters for P-gp-mediated transport, V-max and K-m(app) values. Both Vmax and Km( app) values of each drug were found to show linear correlations with the expression level of P-gp. These findings imply the possibility of estimating the V-max and K-m( app) values of P-gp substrate drugs in the in vivo intestinal membrane on the basis of the P-gp expression level. In the present study, concentration-dependent drug permeability to the rat small intestines ( upper jejunum and ileum) was simulated on the basis of Vmax and Km( app) values of each drug estimated from the P-gp expression level in the rat small intestines. To validate the predictability of these procedures, drug permeability in the rat small intestines was measured by the in situ single-pass perfusion method. It was confirmed that simulated permeability of each drug in the rat jejunum and ileum corresponded well with permeability measured by the in situ single-pass perfusion method. This study clearly demonstrated the potential to estimate the permeability of P-gp substrate drugs in the human intestine from its P-gp expression level and thus the possibility to predict the oral absorption of those drugs.