RT Journal Article SR Electronic T1 Characterization of P-Glycoprotein Humanized Mice Generated by Chromosome Engineering Technology: Its Utility for Prediction of Drug Distribution to the Brain in Humans JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1756 OP 1766 DO 10.1124/dmd.118.081216 VO 46 IS 11 A1 Yuki Yamasaki A1 Kaoru Kobayashi A1 Fuka Okuya A1 Naoyo Kajitani A1 Kanako Kazuki A1 Satoshi Abe A1 Shoko Takehara A1 Shingo Ito A1 Seiryo Ogata A1 Tatsuki Uemura A1 Sumio Ohtsuki A1 Genki Minegishi A1 Hidetaka Akita A1 Kan Chiba A1 Mitsuo Oshimura A1 Yasuhiro Kazuki YR 2018 UL http://dmd.aspetjournals.org/content/46/11/1756.abstract AB P-glycoprotein (P-gp), encoded by the MDR1 gene in humans and by the Mdr1a/1b genes in rodents, is expressed in numerous tissues and performs as an efflux pump to limit the distribution and absorption of many drugs. Owing to species differences of P-gp between humans and rodents, it is difficult to predict the impact of P-gp on pharmacokinetics and the tissue distribution of P-gp substrates in humans from the results of animal experiments. Therefore, we generated a novel P-gp humanized mouse model by using a mouse artificial chromosome (MAC) vector [designated human MDR1-MAC (hMDR1-MAC) mice]. The results showed that hMDR1 mRNA was expressed in various tissues of hMDR1-MAC mice. Furthermore, the expression of human P-gp was detected in the brain capillary fraction and plasma membrane fraction of intestinal epithelial cells isolated from hMDR1-MAC mice, although the expression levels of intestinal P-gp were extremely low. Thus, we evaluated the function of human P-gp at the blood-brain barrier of hMDR1-MAC mice. The brain-to-plasma ratios of P-gp substrates in hMDR1-MAC mice were much lower than those in Mdr1a/1b-knockout mice, and the brain-to-plasma ratio of paclitaxel was significantly increased by pretreatment with a P-gp inhibitor in hMDR1-MAC mice. These results indicated that the hMDR1-MAC mice are the first P-gp humanized mice expressing functional human P-gp at the blood-brain barrier. This mouse is a promising model with which to evaluate species differences of P-gp between humans and mice in vivo and to estimate the brain distribution of drugs in humans while taking into account species differences of P-gp.