For developing oral drugs, it is necessary to predict the oral absorption of new chemical entities accurately. However, it is difficult because of the involvement of efflux transporters, including
P-glycoprotein (P-gp), in their absorption process. In this study, we conducted a comparative analysis on the inhibitory activities of seven P-gp inhibitors (
cyclosporin A,
GF120918,
LY335979,
XR9576, WK-X-34,
VX-710, and OC144-093) to evaluate the effect of P-gp on drug absorption.
GF120918,
LY335979, and
XR9576 significantly decreased the basal-to-apical transport of
paclitaxel, a P-gp substrate, across Caco-2 cell monolayers.
GF120918 also inhibited the basal-to-apical transport of
mitoxantrone, a
breast cancer resistance
protein (BCRP) substrate, in Caco-2 cells, whereas
LY335979 hardly affected the
mitoxantrone transport. In addition, the absorption rate of
paclitaxel after
oral administration in wild-type mice was significantly increased by pretreatment with
LY335979, and it was similar to that in mdr1a/1b knockout mice. Moreover, the absorption rate of
topotecan, a BCRP substrate, in wild-type mice pretreated with
LY335979 was similar to that in mdr1a/1b knockout mice but significantly lower than that in bcrp knockout mice. These results indicate that
LY335979 has a selective inhibitory activity for P-gp, and would be useful for evaluating the contribution of P-gp to drug absorption.