What is the impact of CYP2D6 in the metabolism of selective serotonin reuptake inhibitors (SSRIs)?

Updated: Feb 03, 2021
  • Author: Ali Torkamani, PhD; Chief Editor: Keith K Vaux, MD  more...
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The impact of CYP2D6 activity in drug metabolism is further complicated by the activity of the drug itself on CYP2D6. Some SSRIs, such as paroxetine, fluoxetine, and citalopram, as well as statins, are known to inhibit CYP2D6 activity and may make EMs resemble IMs or PMs. Finally, since most SSRIs are also substrates of CYP2D6, SSRIs that both inhibit and are metabolized by CYP2D6 can inhibit their own metabolism and produce higher than expected plasma concentrations.

More than 100 CYP2D6 variant alleles have been identified. [10] However, 4 of the most prevalent alleles, CYP2D6*3, *4, *5, and *6, accounts for 93 to 97% of PMs. [8]  CYP2D6*4, the most common variant (about 25% frequency in individuals of European ancestry), causes a splicing defect. CYP2D6*3 (2.7% frequency) causes a frameshift mutation, and CYP3D6*5 (2.6%) is an entire deletion of the CYP2D6 gene. Individuals homozygous for these alleles have no CYP2D6 activity. IMs tend to have only one functional copy of CYP2D6, whereas UMs have extra CYP2D6 gene copies.

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