title: Characterization of the inhibition of breast cancer resistance protein-mediated efflux of mitoxantrone by pharmaceutical excipients.
abstract: Previously we showed that some excipients can inhibit breast cancer resistance protein (BCRP/ABCG2) in vitro and in vivo. We then evaluated the reversibility and the mode of BCRP inhibition of excipients, such as Tween 20 and Pluronic P85, by the intracellular mitoxantrone uptake study. To evaluate the reversibility of BCRP inhibitory effects, BCRP expressing cells were preincubated with the excipients and the intracellular mitoxantrone uptake was determined after removing or not removing the excipients. To evaluate the mode of BCRP inhibitory effects, the intracellular mitoxantrone uptake at the different mitoxantrone concentrations in the medium with the excipients was determined. Both Tween 20 and Pluronic P85 increased the mitoxantrone uptake in BCRP expressing cells, but these effects were disappeared when the excipients were removed. Moreover, both excipients increased the uptake at low substrate concentrations. However, at high substrate concentrations, Tween 20 increased the uptake to less extent compared with low substrate concentrations, whereas there was no such effect of Pluronic P85. Taken together, Pluronic P85 and Tween 20 appear to inhibit BCRP-mediated efflux of mitoxantrone reversibly and the inhibition mode of Pluronic P85 may be competitive but not that of Tween 20, which may be mixed type.
authors.affiliation: Department of Pharmaceutics, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Yamagata
authors.forename: Mariko
authors.initials: M
authors.lastname: Morishita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Kozo
authors.initials: K
authors.lastname: Takayama
authors.forename: Hassan
authors.initials: H
authors.lastname: Benameur
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D004285:Dogs; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005079:Excipients / Q000737:chemistry / Q000494:pharmacology*; D008942:Mitoxantrone / Q000737:chemistry / Q000493:pharmacokinetics*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D011060:Poloxalene / Q000737:chemistry / Q000494:pharmacology; D011136:Polysorbates / Q000737:chemistry / Q000494:pharmacology; D014162:Transfection
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D005079:Excipients; D009363:Neoplasm Proteins; D011136:Polysorbates; C422648:pluronic block copolymer p85; D011060:Poloxalene; D008942:Mitoxantrone