Received for publication December 10, 2007.
Revised February 12, 2008.
Accepted for publication February 13, 2008.

SCALING OF IN VITRO MEMBRANE PERMEABILITY TO PREDICT P-GLYCOPROTEIN-MEDIATED DRUG ABSORPTION IN VIVO

Abstract

In a previous study, the concentration-dependent permeability of P-gp substrate drugs, quinidine, verapamil and vinblastine, in several cell monolayers with different levels of P-gp expression was kinetically analyzed to obtain fundamental parameters for P-gp-mediated transport, V_max and K_m(app) values. Both V_max and K_m(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 based on the P-gp expression level. In the present study, concentration-dependent drug permeability to the rat small intestines (upper jejunum and ileum) was simulated based on V_max and K_m(app) values of each drug estimated from P-gp expression level in the rat small intestines. In order to validate the predictability of these procedures, drug permeability in the rat small intestines was measured by 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 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.

Key words: ABC transporters, drug absorption, in vitro-in vivo prediction, in vitro-in vivo scaling, intestinal transport, membrane permeability, oral absorption, p-glycoprotein, pharmacokinetic modeling, pharmacokinetics