Predicting P-glycoprotein effects on oral absorption: correlation of transport in Caco-2 with drug pharmacokinetics in wild-type and mdr1a(-/-) mice in vivo.
OBJECTIVE
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 (R9B-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 RGF 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.


CONCLUSIONS
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.
Collett
Andrew
A
Gut Barrier Group, School of Medicine, University of Manchester, Hope Hospital, Salford M6 8HD, UK.
Tanianis-Hughes
Jolanta
J
Hallifax
David
D
Warhurst
Geoff
G
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000284:Administration, Oral; D000818:Animals; D001693:Biological Transport, Active; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D006801:Humans; D007408:Intestinal Absorption; D051379:Mice; D018345:Mice, Knockout; D010599:Pharmacokinetics; D021241:Spectrometry, Mass, Electrospray Ionization
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; C095122:multidrug resistance protein 3