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 (R_B-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 (r² = 0.8, p < 0.01) was observed between R_GF and R_{KO/WT in vivo}. In contrast, R_B-A/A-B, a more commonly used in vitro measure, showed a much weaker correlation with in vivo data (r² = 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.