TY - JOUR T1 - Characterization of Mdr1a/P-glycoprotein Knockout Rats Generated by Zinc Finger Nucleases JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.111.074179 SP - mol.111.074179 AU - Xiaoyan Chu AU - Zuo Zhang AU - Jocelyn Yabut AU - Sarah Horwitz AU - John Levorse AU - Xiang-qing Li AU - Lei Zhu AU - Harmony Lederman AU - Rachel Ortiga AU - John Strauss AU - Xiaofang Li AU - Karen A Owens AU - Jasminka Dragovic AU - Thomas F Vogt AU - Raymond Evers AU - Myung K Shin Y1 - 2011/11/02 UR - http://molpharm.aspetjournals.org/content/early/2011/11/02/mol.111.074179.abstract N2 - The development of the Zinc Finger Nuclease (ZFN) technology has enabled the genetic engineering of the rat genome. The ability to manipulate the rat genome has great promise to augment the utility of rats for biological and pharmacological studies. A Wistar Hannover rat model lacking the multidrug resistance protein Mdr1a P-glycoprotein (P-gp) was generated using a rat Mdr1a specific ZFN. Mdr1a was completely absent in some tissues, including brain and small intestine, of the knockout rat. Pharmacokinetic studies with the Mdr1a P-gp substrates loperamide, indinavir, and talinolol indicated that Mdr1a was functionally inactive in the blood-brain barrier and intestine in the Mdr1a-/- rats. To identify possible compensatory mechanisms in Mdr1a-/- rats, the expression level of 90 drug metabolizing enzyme and transporter related genes was compared in brain, liver, kidney and intestine of male and female Mdr1a-/- and control rats. In general, alterations in gene expression of these genes in Mdr1a-/- rats appeared to be modest, with more changes in female than in male rats. Taken together, our studies demonstrate that the ZFN generated Mdr1a-/- rat will be a valuable tool for central nervous system (CNS) drug target validation and determining the role of P-gp in drug absorption and disposition ER -