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Does ethnicity impact CYP2D6 genotype-phenotype relationships?

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  • 1Department of Experimental Medicine, H. Lundbeck A/S, Valby, Denmark.

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|March 4, 2023
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Summary

Interethnic differences in cytochrome P450 family 2 subfamily D member 6 (CYP2D6) activity exist, particularly among normal and intermediate metabolizers. These variations are primarily due to differing CYP2D6 allele frequencies across ethnic groups, not enzyme activity differences within identical genotypes.

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Area of Science:

  • Pharmacogenomics
  • Drug Metabolism
  • Population Pharmacokinetics

Background:

  • Cytochrome P450 family 2 subfamily D member 6 (CYP2D6) gene polymorphism significantly impacts enzyme activity, leading to interindividual variability.
  • Despite genotype-based predictions, substantial variability persists within CYP2D6 genotypes, with ethnicity potentially being a contributing factor.

Purpose of the Study:

  • To investigate interethnic differences in CYP2D6 enzyme activity.
  • To analyze CYP2D6 activity across different ethnicities using clinical datasets of three CYP2D6 substrates: brexpiprazole, tedatioxetine, and vortioxetine.

Main Methods:

  • Population pharmacokinetic analyses were used to estimate CYP2D6 activity for all individuals.
  • Individuals were assigned CYP2D6 phenotypes and genotypes.
  • Interethnic differences were investigated within CYP2D6 phenotype and genotype groups.

Main Results:

  • African Americans exhibited lower CYP2D6 activity compared to Asians and Whites among normal metabolizers for tedatioxetine and vortioxetine.
  • Interethnic differences were observed in intermediate metabolizers, though findings varied across substrates.
  • Asian carriers of decreased function CYP2D6 alleles tended to have higher activity than Whites and African Americans.

Conclusions:

  • Observed interethnic differences in CYP2D6 activity within phenotype and genotype groups are mainly driven by variations in CYP2D6 allele frequencies across ethnicities.
  • Ethnicity plays a significant role in CYP2D6 activity, influencing drug response and necessitating consideration in clinical practice.