title: Effect of Knockout of Mdr1a and Mdr1b ABCB1 Genes on the Systemic Exposure of a Doxorubicin-Conjugated Block Copolymer in Mice.
abstract: We previously elucidated that ATP-binding cassette subfamily B member 1 (ABCB1) mediates the efflux of doxorubicin-conjugated block copolymers from HeLa cells. Here, we investigated the role of ABCB1 in the in vivo behavior of a doxorubicin-conjugated polymer in Mdr1a/1b(-/-) mice. The area under the curve for intravenously administered polymer in Mdr1a/1b(-/-) mice was 2.2-fold greater than that in wild-type mice. The polymer was mostly distributed in the liver followed by spleen and less so in the brain, heart, kidney, and lung. The amount of polymer excreted in the urine was significantly decreased in Mdr1a/1b(-/-) mice. The amounts of polymers excreted in the feces were similar in both groups despite the higher systemic exposure in Mdr1a/1b(-/-) mice. Confocal microscopy images showed polymer localized in CD68(+) macrophages in the liver. These results show that knockout of ABCB1 prolonged systemic exposure of the doxorubicin-conjugated polymer in mice. Our results suggest that ABCB1 mediated the excretion of doxorubicin-conjugated polymer in urine and feces. Our results provide valuable information about the behavior of block copolymers in vivo, which is important for evaluating the pharmacokinetics of active substances conjugated to block copolymers or the accumulation of block copolymers in vivo.
authors.affiliation: Division of Drugs, National Institute of Health Sciences , 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Sakai-Kato
authors.affiliation: Division of Drugs, National Institute of Health Sciences , 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan.
authors.forename: Kunie
authors.initials: K
authors.lastname: Nanjo
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.affiliation: Polymer Chemistry Division, Chemical Resources Laboratory, Tokyo Institute of Technology , R1-11, 4259 Nagatsuda, Midori, Yokohama 226-8503, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nishiyama
authors.affiliation: Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo , 7-3-1 Hongo, Bunkyo, Tokyo 113-8656, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
authors.affiliation: National Institute of Health Sciences , 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kawanishi
authors.affiliation: National Institute of Health Sciences , 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan.
authors.forename: Haruhiro
authors.initials: H
authors.lastname: Okuda
authors.affiliation: Division of Drugs, National Institute of Health Sciences , 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Goda
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology*; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000493:pharmacokinetics*; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D011108:Polymers / Q000737:chemistry*; D014018:Tissue Distribution; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D011108:Polymers; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3
keywords: ABCB1; block copolymer micelles; clearance; systemic exposure