title: Characterization of multidrug resistance 1a/P-glycoprotein knockout rats generated by zinc finger nucleases.
abstract: The development of 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 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 Mdr1a(-/-) rats. To identify possible compensatory mechanisms in Mdr1a(-/-) rats, the expression levels of drug-metabolizing enzyme and transporter-related genes were 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 seemed 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 drug target validation and determining the role of P-gp in drug absorption and disposition.
authors: Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. & Inc., Rahway, New Jersey 07065, USA.
authors: Xiaoyan
authors: X
authors: Chu
authors: Zuo
authors: Z
authors: Zhang
authors: Jocelyn
authors: J
authors: Yabut
authors: Sarah
authors: S
authors: Horwitz
authors: John
authors: J
authors: Levorse
authors: Xiang-qing
authors: XQ
authors: Li
authors: Lei
authors: L
authors: Zhu
authors: Harmony
authors: H
authors: Lederman
authors: Rachel
authors: R
authors: Ortiga
authors: John
authors: J
authors: Strauss
authors: Xiaofang
authors: X
authors: Li
authors: Karen A
authors: KA
authors: Owens
authors: Jasminka
authors: J
authors: Dragovic
authors: Thomas
authors: T
authors: Vogt
authors: Raymond
authors: R
authors: Evers
authors: Myung K
authors: MK
authors: Shin
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D004720:Endonucleases; D005260:Female; D015870:Gene Expression; D005818:Genetic Engineering / Q000379:methods*; D016678:Genome; D008297:Male; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar; D014018:Tissue Distribution; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; C095122:multidrug resistance protein 3; D004720:Endonucleases