Gene Knockout Reduces the Metabolism and Efficacy of Venlafaxine in Rats.

Rat has been considered as an ortholog of human To assess the role of CYP2D1 in physiologic processes and drug metabolism, a -null rat model was generated with a CRISPR/Cas9 method. Seven base pairs were deleted from exon 4 of of Sprague-Dawley wild-type (WT) rats. The -null rats were viable and showed no abnormalities in general appearance and behavior. The metabolism of venlafaxine (VLF) was further studied in -null rats. The and intrinsic clearance of the liver microsomes in vitro from -null rats were decreased (by ∼46% and ∼57% in males and ∼47% and ∼58% in females, respectively), while the Michaelis constant was increased (by ∼24% in males and ∼25% in females) compared with WT rats. In the pharmacokinetic studies, compared with WT rats, VLF in -null rats had significantly lower apparent total clearance and apparent volume of distribution (decreased by ∼36% and ∼48% in males and ∼23% and ∼25% in females, respectively), significantly increased area under the curve (AUC) from the time of administration to the last time point, AUC from the start of administration to the theoretical extrapolation, and (increased by ∼64%, ∼59%, and ∼26% in males and ∼43%, ∼35%, and ∼15% in females, respectively). In addition, -desmethyl venlafaxine formation was reduced as well in -null rats compared with that in WT rats. Rat depression models were developed with -null and WT rats by feeding them separately and exposing them to chronic mild stimulation. VLF showed better efficacy in the WT depression rats compared with that in the -null rats. In conclusion, a -null rat model was successfully generated, and CYP2D1 was found to play a certain role in the metabolism and efficacy of venlafaxine. SIGNIFICANCE STATEMENT: A novel -null rat model was generated using CRISPR/Cas9 technology, and it was found to be a valuable tool in the study of the in vivo function of human CYP2D6. Moreover, our data suggest that the reduced -desmethyl venlafaxine formation was associated with a lower VLF efficacy in rats.