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Rat CYP2D1 has been considered as an ortholog of human CYP2D6 To assess the role of CYP2D1 in physiologic processes and drug metabolism, a CYP2D1 -null rat model was generated with a CRISPR/Cas9 method. Seven base pairs were deleted from exon 4 of CYP2D1 of Sprague-Dawley wild-type (WT) rats. The CYP2D1 -null rats were viable and showed no abnormalities in general appearance and behavior. The metabolism of venlafaxine (VLF) was further studied in CYP2D1 -null rats. The V  max and intrinsic clearance of the liver microsomes in vitro from CYP2D1 -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 CYP2D1 -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 C  max (increased by ∼64%, ∼59%, and ∼26% in males and ∼43%, ∼35%, and ∼15% in females, respectively). In addition, O -desmethyl venlafaxine formation was reduced as well in CYP2D1 -null rats compared with that in WT rats. Rat depression models were developed with CYP2D1 -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 CYP2D1 -null rats. In conclusion, a CYP2D1 -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 CYP2D1 -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 O -desmethyl venlafaxine formation was associated with a lower VLF efficacy in rats.

CYP2D1Gene Knockout Reduces the Metabolism and Efficacy of Venlafaxine in Rats