Effect of P-glycoprotein expression levels on the concentration-dependent permeability of drugs to the cell membrane

The purpose of this study is to develop a kinetic model that can predict the in vivo absorption of P-glycoprotein (P-gp) substrates from in vitro data. Apical (A-P) to basal (BL) absorptive permeability of typical P-gp substrate drugs including quinidine, verapamil, vinblastine, and digoxin, were measured in several cell monolayers with different levels of P-gp expression, normal, P-gp induced, P-gp highly induced and MDR1-knockdown Caco-2 cells and MDR1-MDCKII cells. In all cell monolayers, AP to BL permeability of P-gp substrates increased when their A-P concentration was increased, showing a sigmoid-type relationship to donor (A-P) concentrations. At the higher concentration range, permeability reached a maximum value, suggesting saturation of P-gp-mediated efflux, and at the lower concentration range, permeability decreased depending on P-gp expression level. A simple kinetic model was applied to the permeability-concentration curve of each drug to obtain the fundamental parameters for P-gp-mediated transport, K-m(app) and V-max. Both K-m(app) and V-max of each drug were found to show linear correlations with expression level of P-gp. This study clearly demonstrated the possibility to estimate the permeability of P-gP substrate drugs in human intestine from the expression level of P-gp, and thus the possibility to predict oral absorption of those drugs. (C) 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:553-565, 2008.