PT  - JOURNAL ARTICLE
AU  - Yamasaki, Yuki
AU  - Kobayashi, Kaoru
AU  - Okuya, Fuka
AU  - Kajitani, Naoyo
AU  - Kazuki, Kanako
AU  - Abe, Satoshi
AU  - Takehara, Shoko
AU  - Ito, Shingo
AU  - Ogata, Seiryo
AU  - Uemura, Tatsuki
AU  - Ohtsuki, Sumio
AU  - Minegishi, Genki
AU  - Akita, Hidetaka
AU  - Chiba, Kan
AU  - Oshimura, Mitsuo
AU  - Kazuki, Yasuhiro
TI  - Characterization of P-glycoprotein Humanized Mice Generated by Chromosome Engineering Technology: Its Utility for Prediction of Drug Distribution to the Brain in Humans
AID  - 10.1124/dmd.118.081216
DP  - 2018 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.118.081216
4099  - http://dmd.aspetjournals.org/content/early/2018/05/18/dmd.118.081216.short
4100  - http://dmd.aspetjournals.org/content/early/2018/05/18/dmd.118.081216.full
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 plays 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 tissue distribution of P-gp substrates in humans from 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, expression of human P-gp protein 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 protein 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 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.