Journal
PHARMACEUTICS
Volume 13, Issue 3, Pages -Publisher
MDPI
DOI: 10.3390/pharmaceutics13030388
Keywords
intestinal absorption; P-glycoprotein; breast cancer resistance protein; LY335979; WK-X-34
Categories
Funding
- Strategic Research Foundation at Private Universities [17K08430]
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Ritsumeikan Global Innovation Research Organization (R-GIRO) Project at Ritsumeikan University
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The study compared the inhibitory activities of seven P-gp inhibitors on drug absorption and found that LY335979 has selective inhibitory activity for P-glycoprotein, which can be used to evaluate the contribution of P-gp to drug absorption.
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.
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