TY - JOUR 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 SP - 1756 LP - 1766 DO - 10.1124/dmd.118.081216 VL - 46 IS - 11 AU - Yuki Yamasaki AU - Kaoru Kobayashi AU - Fuka Okuya AU - Naoyo Kajitani AU - Kanako Kazuki AU - Satoshi Abe AU - Shoko Takehara AU - Shingo Ito AU - Seiryo Ogata AU - Tatsuki Uemura AU - Sumio Ohtsuki AU - Genki Minegishi AU - Hidetaka Akita AU - Kan Chiba AU - Mitsuo Oshimura AU - Yasuhiro Kazuki Y1 - 2018/11/01 UR - http://dmd.aspetjournals.org/content/46/11/1756.abstract N2 - 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. ER -