TY - JOUR T1 - Development and characterization of MDR1 (Mdr1a/b) CRISPR/Cas9 knockout rat model JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.118.084277 SP - dmd.118.084277 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 - 2018/01/01 UR - http://dmd.aspetjournals.org/content/early/2018/11/26/dmd.118.084277.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 multidrug resistance. In this report, a novel MDR1 (Mdr1a/b) double knockout (KO) rat model was generated by CRISPR/Cas9 system without any off-target effect detected. Western blot results showed that MDR1 was completely absent in 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 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 multidrug resistance and drug target validation. ER -