title: Improvement of the oral drug absorption of topotecan through the inhibition of intestinal xenobiotic efflux transporter, breast cancer resistance protein, by excipients.
abstract: Recently, breast cancer resistance protein (BCRP/ABCG2) has been shown to limit the oral absorption of its substrates in the intestine. The purpose of this study was to examine whether excipients can be used as inhibitors of BCRP, to improve the oral drug absorption of BCRP substrates. In wild-type mice, Pluronic P85 and Tween 20, given orally 15 min before topotecan administration, increased the area under the plasma concentration-time curve (AUC) of topotecan after oral administration (2.0- and 1.8-fold, respectively). In contrast, Pluronic P85 and Tween 20 were less effective (no significant difference) on the AUC of topotecan after oral administration in Bcrp (-/-) mice (1.2- and 1.2-fold, respectively). Pluronic P85 and Tween 20 given orally did not affect significantly the AUC of topotecan after intravenous administration in wild-type and Bcrp (-/-) mice. Moreover, we determined the mucosal-to-serosal absorptive transport of topotecan using everted mouse ileum. Pluronic P85 and Tween 20 significantly increased the intestinal absorption rate of topotecan in everted sacs from wild-type mice whereas, in everted sacs from Bcrp (-/-) mice, the absorption rate was 2.1-fold greater than that in wild-type mice, and these excipients were not significantly effective. There was no significant difference in the intestinal P-glycoprotein (P-gp) expression and serosal-to-mucosal secretory transport of rhodamine 123, a typical P-gp substrate. Taken together, these results suggest that Pluronic P85 and Tween 20 can improve the oral bioavailability of BCRP substrates by inhibiting BCRP function in the small intestine.
authors: Department of Pharmaceutics, Hoshi University, Shinagawa, Tokyo 142-8501, Japan.
authors: Tetsuo
authors: T
authors: Yamagata
authors: Hiroyuki
authors: H
authors: Kusuhara
authors: Mariko
authors: M
authors: Morishita
authors: Kozo
authors: K
authors: Takayama
authors: Hassan
authors: H
authors: Benameur
authors: Yuichi
authors: Y
authors: Sugiyama
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D005079:Excipients / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D011060:Poloxalene / Q000494:pharmacology*; D011136:Polysorbates / Q000494:pharmacology*; D019772:Topotecan / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000970:Antineoplastic Agents; D005079:Excipients; D011136:Polysorbates; C422648:pluronic block copolymer p85; D019772:Topotecan; D011060:Poloxalene