Phenotype:CYP2D6 ultrarapid metabolizer

A CYP2D6 ultrarapid metabolizer (UM) is a person whose CYP2D6 alleles together produce greater-than-normal enzyme activity. It is the highest-activity of the four metabolizer phenotypes assigned from CYP2D6 genotype, above the normal metabolizer, intermediate metabolizer, and poor metabolizer. In the activity-score system that translates CYP2D6 genotype into a phenotype, an ultrarapid metabolizer has a score above 2.25. This page describes the ultrarapid-metabolizer phenotype; the enzyme itself is covered at Enzyme:CYP2D6.

The ultrarapid metabolizer is the mirror image of the poor metabolizer, and it carries the single most clinically urgent fact in CYP2D6 pharmacogenomics. The two-directional logic still applies, but reversed: a medicine that CYP2D6 activates is activated too fast and too far, and a medicine that CYP2D6 clears is cleared so quickly that it may never reach a working concentration. The first of these is a safety problem, and a serious one.

Genotype basis

The ultrarapid-metabolizer phenotype is usually produced not by a special point variant but by gene duplication: an individual carries more than two copies of a functional CYP2D6 allele, written \*1xN or \*2xN, where N is the number of copies. Each additional functional copy adds its activity value to the total, pushing the activity score above the normal 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 ultrarapid-metabolizer phenotype is found in roughly 1 to 5% of European-ancestry populations and less than 1% of East Asian populations, but it reaches much higher frequencies in some North African, Middle Eastern, and East African populations, up to around 28% in parts of Ethiopia. Any account of CYP2D6 phenotype frequency that quotes only European-ancestry figures will badly understate the prevalence of this phenotype in the populations where it is most common.

Clinical consequences

Medicines that CYP2D6 activates: the safety problem. For the opioid prodrugs codeine and tramadol, an ultrarapid metabolizer converts the prodrug to its active opioid form rapidly and excessively. With codeine, this means a fast, large generation of morphine, and it can produce opioid toxicity and life-threatening respiratory depression at ordinary doses. This is not a theoretical concern: it is the basis of the FDA's restriction of codeine in children and the warnings against codeine use in breastfeeding mothers, in whom morphine generated from codeine passes into breast milk and has caused infant deaths. CPIC strongly recommends avoiding codeine and tramadol in CYP2D6 ultrarapid metabolizers and using an analgesic that does not depend on CYP2D6 activation.

Medicines that CYP2D6 clears: the efficacy problem. For the tricyclic antidepressants and other medicines eliminated through CYP2D6, an ultrarapid metabolizer clears the medicine so quickly that a standard dose may produce a subtherapeutic plasma concentration and an apparent failure of treatment. CPIC recommends considering an alternative medicine not metabolized by CYP2D6, or close monitoring with the expectation that a higher dose may be required.

See also

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