Predicting P-glycoprotein effects on oral absorption:: Correlation of transport in Caco-2 with drug pharmacokinetics in wild-type and mdr1a(-/-) mice in vivo

Purpose. Cell-based permeability screens are widely used to identify drug-P-glycoprotein (PGP) interaction in vitro. However, their reliability in predicting the impact of PGP on human drug pharmacokinetics is poorly defined. The aim was to determine whether a quantitative relationship exists between PGP-mediated alterations in Caco-2 permeability and oral pharmacokinetics in mice. Methods. Two indicators of drug efflux were measured in Caco-2 for a group of 10 compounds, the ratio of A-B and B-A transport (RB-A/A-B) and the ratio of A-B transport in the presence and absence of a PGP inhibitor, GF120918 (R-GF). These data were correlated with ratios of oral plasma levels in either mdr1a(-/-) or mdr1a/1b(-/-) and wild-type mice (R-KO/WT in vivo) calculated from literature data on these compounds. Results. A significant, positive correlation (r(2) = 0.8, p < 0.01) was observed between R-GF and R-KO/WT in vivo. In contrast, RB-A/A-B, a more commonly used in vitro measure, showed a much weaker correlation with in vivo data (r(2) = 0.33, p = 0.11). A strong correlation with R-GF was also observed after correction of in vivo data for PGP effects on IV clearance. Conclusion. The increase in A-B drug permeability following inhibition of PGP in Caco-2 allows a reasonable prediction of the likely in vivo impact that PGP will have on plasma drug levels after oral administration.