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

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Yuki YamasakiYasuhiro Kazuki

Abstract

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 in...Continue Reading

References

Mar 4, 1997·Proceedings of the National Academy of Sciences of the United States of America·A SparreboomO van Tellingen
Apr 15, 1997·Proceedings of the National Academy of Sciences of the United States of America·A H SchinkelP Borst
Apr 12, 2001·The Journal of Biological Chemistry·A GeickO Burk
Sep 25, 2001·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·A Ayrton, P Morgan
Feb 14, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Cuiping ChenJae S Lee
Apr 23, 2005·Toxicology and Applied Pharmacology·Elaine M LeslieSusan P C Cole
Jun 18, 2005·Clinical Pharmacology and Therapeutics·Lucy SasongkoJashvant D Unadkat
Nov 28, 2006·Expert Opinion on Drug Metabolism & Toxicology·Marcella MartignoniRuben de Kanter
Oct 27, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Bo FengSonia M de Morais
Dec 25, 2007·Journal of Clinical Pharmacology·Richard CallaghanIan D Kerr
Jan 11, 2008·Journal of Proteome Research·Takeshi MasudaYasushi Ishihama
Jul 21, 2009·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Mark MuziJashvant D Unadkat
Nov 17, 2009·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Claudia C WagnerOliver Langer
Jan 9, 2010·European Journal of Clinical Investigation·UNKNOWN Italian Medicines Agency (AIFA) Research & Development Working Group
Mar 2, 2010·Nature Reviews. Drug Discovery·UNKNOWN International Transporter ConsortiumLei Zhang
Mar 11, 2010·Pharmacogenetics and Genomics·Laura M HodgesRuss B Altman
Dec 21, 2010·Trends in Pharmacological Sciences·Dolores D MrukC Yan Cheng
Feb 5, 2011·Journal of Neurochemistry·Yasuo UchidaTetsuya Terasaki
Aug 25, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Nico ScheerC Roland Wolf
Dec 22, 2012·Expert Opinion on Drug Metabolism & Toxicology·Xiaoyan ChuRaymond Evers
May 10, 2013·ACS Synthetic Biology·Masato TakiguchiMitsuo Oshimura
Jun 21, 2014·The Journal of Pharmacology and Experimental Therapeutics·Yasuo UchidaTetsuya Terasaki
Dec 2, 2014·Pharmacology & Therapeutics·Renata SilvaFernando Remião
Feb 7, 2015·Chromosome Research : an International Journal on the Molecular, Supramolecular and Evolutionary Aspects of Chromosome Biology·Mitsuo OshimuraToshiaki Inoue
Feb 12, 2015·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Martin BauerOliver Langer
Feb 20, 2016·Molecular Pharmacology·Shannon DallasNico Scheer
Feb 6, 2018·Drug Metabolism and Pharmacokinetics·Daisuke SatohYasuhiro Kazuki

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Citations

Oct 20, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Aarti Sawant-Basak, R Scott Obach
Nov 2, 2019·CPT: Pharmacometrics & Systems Pharmacology·Qiang FuShuiying Hu
Dec 19, 2018·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Genki MinegishiKaoru Kobayashi
Jul 25, 2020·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Seiryo OgataSumio Ohtsuki
Dec 2, 2020·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Yingying ZhaoYong Lai
Mar 7, 2020·Experimental Cell Research·Takashi MoriwakiYasuhiro Kazuki

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