Effect of Knockout of Mdr1a and Mdr1b ABCB1 Genes on the Systemic Exposure of a Doxorubicin-Conjugated Block Copolymer in Mice

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• 作者：Kumiko Sakai-Kato ; Kunie Nanjo ; Hiroyuki Kusuhara ; Nobuhiro Nishiyama ; Kazunori Kataoka ; Toru Kawanishi ; Haruhiro Okuda ; Yukihiro Goda
• 刊名：Molecular Pharmaceutics
• 出版年：2015
• 出版时间：September 8, 2015
• 年：2015
• 卷：12
• 期：9
• 页码：3175-3183
• 全文大小：418K
• ISSN：1543-8392

文摘

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(鈭?鈭? mice. The area under the curve for intravenously administered polymer in Mdr1a/1b(鈭?鈭? 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(鈭?鈭? mice. The amounts of polymers excreted in the feces were similar in both groups despite the higher systemic exposure in Mdr1a/1b(鈭?鈭? 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.