Phenotype:CYP2D6 poor metabolizer

A CYP2D6 poor metabolizer (PM) is a person who carries two non-functional CYP2D6 alleles and therefore produces little or no functional CYP2D6 enzyme. It is one of the four metabolizer phenotypes assigned from CYP2D6 genotype, the others being the intermediate metabolizer, the normal metabolizer, and the ultrarapid metabolizer. In the activity-score system that translates CYP2D6 genotype into a phenotype, a poor metabolizer has an activity score of zero. This page describes the poor-metabolizer phenotype; the enzyme itself, its history, and its full substrate range are covered at Enzyme:CYP2D6.

The clinical importance of the poor-metabolizer phenotype runs in two opposite directions, and which direction applies depends entirely on what CYP2D6 does to the medicine in question. For a medicine that CYP2D6 activates from an inactive prodrug into its working form, the poor metabolizer generates too little of the active form and the medicine underperforms. For a medicine that CYP2D6 clears from the body, the poor metabolizer cannot clear it at the normal rate, the medicine accumulates, and the risk is toxicity. A clinician who knows a patient is a CYP2D6 poor metabolizer has to ask, for each affected medicine, which of these two cases applies.

Genotype basis

The poor-metabolizer phenotype is produced by a CYP2D6 diplotype in which both alleles are no-function alleles, each contributing an activity value of zero. The no-function alleles encountered most often are:

• \*3 (a frameshift variant), no function.
• \*4 (a splice-defect variant), no function, and the most common no-function allele in European-ancestry populations.
• \*5 (a deletion of the entire CYP2D6 gene), no function.
• \*6 (a frameshift variant), no function.

Any pairing of two such alleles (for example \*4/\*4, \*4/\*5, \*3/\*4, \*5/\*6) produces an activity score of zero and the poor-metabolizer phenotype. A diplotype that pairs a no-function allele with a decreased-function allele (such as \*4/\*10) produces a non-zero activity score and is classified as an intermediate metabolizer, not a poor metabolizer. The full allele catalogue and the activity-score scheme are maintained at PharmVar and described on the Enzyme:CYP2D6 page.

Population frequency

The CYP2D6 poor-metabolizer phenotype is found in roughly 5 to 10% of European-ancestry populations, 1 to 2% of East Asian populations, and 3 to 8% of African-ancestry populations. The frequency variation reflects the different distributions of the underlying no-function alleles between populations, and it is one reason that ancestry-aware genotyping panels matter: a panel built around the no-function alleles common in one population will under-detect the phenotype in another.

Clinical consequences

The clinical guidance below follows the Clinical Pharmacogenetics Implementation Consortium (CPIC), which publishes phenotype-specific recommendations for the medicines on which CYP2D6 genotype acts most strongly.

Medicines that CYP2D6 activates (the phenotype reduces effect).

• Codeine and Tramadol are opioid prodrugs that CYP2D6 converts into their active forms (morphine and O-desmethyltramadol respectively). A poor metabolizer generates little or none of the active opioid and obtains little or no analgesia. CPIC recommends avoiding codeine and tramadol in CYP2D6 poor metabolizers and selecting an analgesic that does not depend on CYP2D6 activation.

Medicines that CYP2D6 clears (the phenotype raises exposure).

• The tricyclic antidepressants (amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, doxepin) depend substantially on CYP2D6 for clearance. A poor metabolizer reaches higher plasma concentrations at a standard dose; CPIC recommends a reduced starting dose, on the order of half the usual dose, with therapeutic drug monitoring, or an alternative antidepressant.
• Atomoxetine exposure is markedly higher in poor metabolizers; CPIC recommends a reduced dose and slower titration.
• Several antipsychotics eliminated through CYP2D6 (aripiprazole, brexpiprazole, pimozide, haloperidol) accumulate in poor metabolizers, and FDA labeling for some of them specifies dose reductions or caps in this phenotype.

The general rule for the poor metabolizer is conservative: for a CYP2D6-activated prodrug, expect underperformance and choose another medicine; for a CYP2D6-cleared medicine with a narrow therapeutic window, start low and monitor.

Phenocopying

A person who is genetically a normal metabolizer can be converted, in functional terms, into a poor metabolizer by a strong CYP2D6 inhibitor. Co-prescription of fluoxetine, paroxetine, or bupropion, all strong CYP2D6 inhibitors, suppresses CYP2D6 activity enough that the patient behaves, for the duration of the inhibition, as a poor metabolizer. This is called phenocopying, and it means the clinical picture described on this page can arise from a drug interaction in a genetically normal patient, not only from inherited genotype. The phenocopy is described more fully on the Enzyme:CYP2D6 page.

See also

• Enzyme:CYP2D6, the enzyme, its history, and its full substrate spectrum.
• Phenotype:CYP2D6 intermediate metabolizer, Phenotype:CYP2D6 normal metabolizer, Phenotype:CYP2D6 ultrarapid metabolizer, the sibling phenotypes.
• Codeine, Tramadol (the activation case), Amitriptyline, Atomoxetine (the clearance case).
• Category:Pharmacogenomic phenotypes