TY - JOUR T1 - Generation and Characterization of a CYP2C11-Null Rat Model by Using the CRISPR/Cas9 Method JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 525 LP - 531 DO - 10.1124/dmd.117.078444 VL - 46 IS - 5 AU - Yuan Wei AU - Li Yang AU - Xiaoyan Zhang AU - Danjuan Sui AU - Changsuo Wang AU - Kai Wang AU - Mangting Shan AU - Dayong Guo AU - Hongyu Wang Y1 - 2018/05/01 UR - http://dmd.aspetjournals.org/content/46/5/525.abstract N2 - CYP2C11 is involved in the metabolism of many drugs in rats. To assess the roles of CYP2C11 in physiology and drug metabolism, a CYP2C11-null rat model was generated using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 method. A 2-base pair insertion was added to exon 6 of CYP2C11 in Sprague-Dawley rats. CYP2C11 was not detected by western blotting in liver microsomes of CYP2C11-null rats. No off-target effects were found at 11 predicted sites of the knockout model. The CYP2C11-null rats were viable and had no obvious abnormalities, with the exception of reduced fertility. Puberty in CYP2C11-null rats appeared to be delayed by ∼20 days, and the average litter size fell by 43%. Tolbutamide was used as a probe in this drug metabolism study. In the liver microsomes of CYP2C11-null rats, the Vmax and intrinsic clearance values decreased by 22% and 47%, respectively, compared with those of wild-type rats. The Km values increased by 47% compared with that of wild types. However, our pharmacokinetics study showed no major differences in any parameters between the two strains, in both males and females. In conclusion, a CYP2C11-null rat model was successfully generated and is a valuable tool to study the in vivo function of CYP2C11. ER -