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 dmd.118.081216
DO 10.1124/dmd.118.081216
A1 Yamasaki, Yuki
A1 Kobayashi, Kaoru
A1 Okuya, Fuka
A1 Kajitani, Naoyo
A1 Kazuki, Kanako
A1 Abe, Satoshi
A1 Takehara, Shoko
A1 Ito, Shingo
A1 Ogata, Seiryo
A1 Uemura, Tatsuki
A1 Ohtsuki, Sumio
A1 Minegishi, Genki
A1 Akita, Hidetaka
A1 Chiba, Kan
A1 Oshimura, Mitsuo
A1 Kazuki, Yasuhiro
YR 2018
UL http://dmd.aspetjournals.org/content/early/2018/05/18/dmd.118.081216.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 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.