Phenotype:CYP2D6 intermediate metabolizer

A CYP2D6 intermediate metabolizer (IM) is a person whose CYP2D6 alleles together produce reduced, but not absent, enzyme activity. It is one of the four metabolizer phenotypes assigned from CYP2D6 genotype, sitting between the poor metabolizer (no activity) and the normal metabolizer (typical activity), with the ultrarapid metabolizer above. In the activity-score system that translates CYP2D6 genotype into a phenotype, an intermediate metabolizer has a score above zero and up to 1.25. This page describes the intermediate-metabolizer phenotype; the enzyme itself is covered at Enzyme:CYP2D6.

The intermediate metabolizer is, in clinical terms, a milder version of the poor metabolizer. The same two-directional logic applies: a medicine that CYP2D6 activates is activated incompletely, and a medicine that CYP2D6 clears is cleared slowly. The difference is one of degree. Where a poor metabolizer may obtain no effect from a CYP2D6-activated prodrug, an intermediate metabolizer obtains a reduced effect; where a poor metabolizer accumulates a CYP2D6-cleared medicine substantially, an intermediate metabolizer accumulates it modestly.

Genotype basis

The intermediate-metabolizer phenotype is produced by a CYP2D6 diplotype that combines either one no-function allele with one decreased-function allele, or two decreased-function alleles. The decreased-function alleles encountered most often are:

• \*10 (activity value 0.25), the most common decreased-function allele in East Asian populations.
• \*17 (activity value 0.5), most common in African-ancestry populations.
• \*41 (activity value 0.25).

Diplotypes such as \*4/\*10, \*4/\*41, \*10/\*10, \*10/\*41, and \*17/\*17 produce an activity score in the intermediate range. The full allele catalogue and the activity-score scheme are maintained at PharmVar and described on the Enzyme:CYP2D6 page.

Population frequency

The CYP2D6 intermediate-metabolizer phenotype is found in roughly 10 to 17% of European-ancestry populations, 30 to 50% of East Asian populations, and 20 to 35% of African-ancestry populations. The phenotype is markedly more common in East Asian populations than in European-ancestry populations, driven by the high frequency of the \*10 decreased-function allele in East Asia.

Clinical consequences

The clinical guidance below follows the Clinical Pharmacogenetics Implementation Consortium (CPIC).

Medicines that CYP2D6 activates. For the opioid prodrugs codeine and tramadol, an intermediate metabolizer generates a reduced quantity of the active opioid metabolite. Many intermediate metabolizers obtain adequate analgesia, but some do not, and CPIC advises using these medicines with the awareness that response may be reduced, monitoring the analgesic effect, and switching to a non-CYP2D6 analgesic if it is inadequate.

Medicines that CYP2D6 clears. For the tricyclic antidepressants and other medicines eliminated through CYP2D6, an intermediate metabolizer reaches modestly higher plasma concentrations than a normal metabolizer at the same dose. CPIC guidance for intermediate metabolizers is generally less aggressive than for poor metabolizers: a modest dose reduction or simply closer monitoring, rather than the substantial reductions advised for poor metabolizers.

Phenocopying

An intermediate metabolizer co-prescribed a strong CYP2D6 inhibitor (fluoxetine, paroxetine, bupropion) can be pushed functionally into the poor-metabolizer range for the duration of the inhibition. Because the intermediate metabolizer already starts with reduced activity, the margin before a clinically significant loss of function is smaller than it is for a normal metabolizer.

See also

• Enzyme:CYP2D6, the enzyme, its history, and its full substrate spectrum.
• Phenotype:CYP2D6 poor metabolizer, Phenotype:CYP2D6 normal metabolizer, Phenotype:CYP2D6 ultrarapid metabolizer, the sibling phenotypes.
• Codeine, Tramadol, Amitriptyline (representative affected medicines).
• Category:Pharmacogenomic phenotypes