Characterization of P-Glycoprotein Humanized Mice Generated by Chromosome Engineering Technology: Its Utility for Prediction of Drug Distribution to the Brain in Humans

• DOI: 10.1124/dmd.118.081216
• Publication Date: 2018-05-18T18:00:37Z
• Authors: Yuki Yamasaki; Kaoru Kobayashi; Fuka Okuya; Naoyo Kajitani; Kanako Kazuki; Satoshi Abe; Shoko Takehara; Shingo Ito; Seiryo Ogata; Tatsuki Uemura; Sumio Ohtsuki; Genki Minegishi; Hidetaka Akita; Kan Chiba; Mitsuo Oshimura; Yasuhiro Kazuki
• Keywords: P-glycoprotein; Humanized mouse; Knockout mouse; Efflux; Gene knockout; Biodistribution

P-glycoprotein (P-gp), encoded by the <i>MDR1</i> gene in humans and <i>Mdr1a</i>/<i>1b</i> genes rodents, is expressed numerous tissues performs as an efflux pump to limit distribution absorption of many drugs. Owing species differences P-gp between it difficult predict impact on pharmacokinetics tissue substrates from results animal experiments. Therefore, we generated a novel humanized mouse model using artificial chromosome (MAC) vector [designated human MDR1-MAC (hMDR1-MAC) mice]. The showed that hMDR1 mRNA was various hMDR1-MAC mice. Furthermore, expression detected brain capillary fraction plasma membrane intestinal epithelial cells isolated mice, although levels were extremely low. Thus, evaluated function at blood-brain barrier brain-to-plasma ratios mice much lower than those Mdr1a/1b-knockout ratio paclitaxel significantly increased pretreatment with inhibitor These indicated are first expressing functional barrier. This promising which evaluate vivo estimate drugs while taking into account P-gp.