TY - JOUR T1 - Development and Characterization of MDR1 (<em>Mdr1a/b</em>) CRISPR/Cas9 Knockout Rat Model JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 71 LP - 79 DO - 10.1124/dmd.118.084277 VL - 47 IS - 2 AU - Chenmeizi Liang AU - Junfang Zhao AU - Jian Lu AU - Yuanjin Zhang AU - Xinrun Ma AU - Xuyang Shang AU - Yongmei Li AU - Xueyun Ma AU - Mingyao Liu AU - Xin Wang Y1 - 2019/02/01 UR - http://dmd.aspetjournals.org/content/47/2/71.abstract N2 - Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) technology is widely used as a tool for gene editing in rat genome site-specific engineering. Multidrug resistance 1 [MDR1 (also known as P-glycoprotein)] is a key efflux transporter that plays an important role not only in the transport of endogenous and exogenous substances, but also in tumor MDR. In this report, a novel MDR1 (Mdr1a/b) double-knockout (KO) rat model was generated by the CRISPR/Cas9 system without any off-target effect detected. Western blot results showed that MDR1 was completely absent in the liver, small intestine, brain, and kidney of KO rats. Further pharmacokinetic studies of digoxin, a typical substrate of MDR1, confirmed the deficiency of MDR1 in vivo. To determine the possible compensatory mechanism of Mdr1a/b (−/−) rats, the mRNA levels of the CYP3A subfamily and transporter-related genes were compared in the brain, liver, kidney, and small intestine of KO and wild-type rats. In general, a new Mdr1a/b (−/−) rat model has been successfully generated and characterized. This rat model is a useful tool for studying the function of MDR1 in drug absorption, tumor MDR, and drug target validation. ER -