Abstract
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 Vmax 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 Cmax (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.
Footnotes
- Received June 28, 2019.
- Accepted October 9, 2019.
This study was supported by the National Natural Science Foundation of China [Grants 81102522, 81373480, and 81573529], and the Natural Science Foundation of Jiangsu Province [Grant BK2011473].
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This article has supplemental material available at dmd.aspetjournals.org.
- Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics
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