Predicting P-Glycoprotein Effects on Oral Absorption: Correlation of Transport in Caco-2 with Drug Pharmacokinetics in Wild-Type and mdr1a(-/-) Mice in Vivo

Andrew Collett, Jolanta Tanianis-Hughes, David Hallifax, Geoff Warhurst

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52 Citations (Scopus)


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 (RGF). 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 RGF and RKO/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 (r2 = 0.33. p = 0.11). A strong correlation with RGF 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.

Original languageEnglish
Pages (from-to)819-826
Number of pages8
JournalPharmaceutical Research
Issue number5
Publication statusPublished - May 2004
Externally publishedYes


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