Phenotype:CYP2D6 normal metabolizer

A CYP2D6 normal metabolizer (NM) is a person whose CYP2D6 alleles together produce the typical, reference level of enzyme activity. It is the most common of the four metabolizer phenotypes assigned from CYP2D6 genotype, with the poor metabolizer and intermediate metabolizer below it and the ultrarapid metabolizer above. In the activity-score system that translates CYP2D6 genotype into a phenotype, a normal metabolizer has a score above 1.25 and up to 2.25. This page describes the normal-metabolizer phenotype; the enzyme itself is covered at Enzyme:CYP2D6.

The normal metabolizer is the reference phenotype, and that fact is the most important thing about it: the standard, label-recommended doses of CYP2D6-affected medicines were established in, and are calibrated to, normal-metabolizer populations. For a normal metabolizer, CYP2D6 genotype is not a reason to depart from standard dosing.

Genotype basis

The normal-metabolizer phenotype is produced by a CYP2D6 diplotype whose activity score falls in the normal range, most often a pairing of two normal-function alleles such as \*1/\*1, \*1/\*2, or \*2/\*2. Certain combinations that include an increased-function allele, or a normal-function allele paired with a decreased-function allele, can also land within the normal range. The full allele catalogue and the activity-score scheme are maintained at PharmVar and described on the Enzyme:CYP2D6 page.

A point of terminology: the normal-metabolizer phenotype was formerly called the extensive metabolizer (EM). The label was changed to "normal metabolizer" in the 2019 harmonization of phenotype nomenclature between CPIC and the Dutch Pharmacogenetics Working Group, because "extensive" was being read by clinicians as "greater than normal" when it in fact meant "typical".

Population frequency

The CYP2D6 normal-metabolizer phenotype is found in roughly 65 to 80% of European-ancestry populations, 45 to 65% of East Asian populations, and 50 to 70% of African-ancestry populations. It is the majority phenotype in every well-studied population.

Clinical significance

For a CYP2D6 normal metabolizer, standard dosing of CYP2D6-affected medicines applies, and no genotype-based dose adjustment is indicated. Two caveats are nonetheless worth stating.

First, the normal metabolizer is the phenotype most often altered by a drug interaction. A normal metabolizer co-prescribed a strong CYP2D6 inhibitor (fluoxetine, paroxetine, bupropion) is converted, functionally, into an intermediate or poor metabolizer for the duration of the inhibition. The genotype says normal; the working phenotype, in the presence of the inhibitor, is not. This is called phenocopying and it is described on the Enzyme:CYP2D6 page.

Second, being a normal metabolizer removes CYP2D6 genotype as a source of concern but does not remove the other sources of variability in a medicine's effect: drug interactions, age, organ function, adherence, and the rest. Normal-metabolizer status is reassurance about one variable, not all of them.

See also

• Enzyme:CYP2D6, the enzyme, its history, and its full substrate spectrum.
• Phenotype:CYP2D6 poor metabolizer, Phenotype:CYP2D6 intermediate metabolizer, Phenotype:CYP2D6 ultrarapid metabolizer, the sibling phenotypes.
• Category:Pharmacogenomic phenotypes