Phenotype:CYP3A4 intermediate metabolizer
A CYP3A4 intermediate metabolizer (IM) is a person who carries one normal-function and one decreased-function CYP3A4 allele, and therefore has somewhat reduced CYP3A4 enzyme activity. It is one of the three metabolizer phenotypes assigned from CYP3A4 genotype under the framework of the Dutch Pharmacogenetics Working Group (DPWG), sitting between the poor metabolizer and the normal metabolizer. This page describes the intermediate-metabolizer phenotype; the enzyme itself is covered at Enzyme:CYP3A4.
As noted on the poor-metabolizer page, the CYP3A4 phenotype classification is a DPWG construct and is not endorsed by the Clinical Pharmacogenetics Implementation Consortium, which does not tier CYP3A4. The CYP3A4 intermediate-metabolizer phenotype should be read as a less settled construct than the corresponding phenotypes of CYP2D6 or CYP2C19.
Genotype basis
The intermediate-metabolizer phenotype is produced by the \*1/\*22 diplotype: one normal-function allele paired with one copy of the decreased-function CYP3A4\*22 allele (rs35599367), an intron-6 variant that reduces CYP3A4 transcription.[1] The full allele catalogue is described on the Enzyme:CYP3A4 page.
Population frequency
Because the \*22 allele has a frequency of roughly 5 to 8% in European-ancestry populations, the intermediate-metabolizer phenotype, carrying a single copy, is the most commonly encountered reduced CYP3A4 phenotype, more common than the poor-metabolizer phenotype that requires two copies. It is uncommon in populations where \*22 is rare.
Clinical consequences
A CYP3A4 intermediate metabolizer clears CYP3A4-cleared medicines somewhat more slowly than a normal metabolizer, reaching modestly higher exposures. The clinical action attached to this is limited. The DPWG guideline that defines the CYP3A4 phenotype directs its dosing changes mainly at the poor-metabolizer end; for quetiapine, for instance, the DPWG advises an alternative medicine for poor metabolizers but states that no action is needed for intermediate metabolizers.[2]
The caveat stated on the poor-metabolizer page applies here with even more force: the modest genetic effect of a single \*22 allele is small next to the effect of CYP3A4 induction and inhibition by co-prescribed medicines and by grapefruit. For an intermediate metabolizer, the CYP3A4 drug-interaction picture is almost always the dominant determinant of CYP3A4 activity, and the \*1/\*22 genotype is a minor contributing factor.
See also
- Enzyme:CYP3A4, the enzyme, its history, and its full substrate spectrum.
- Phenotype:CYP3A4 poor metabolizer, Phenotype:CYP3A4 normal metabolizer, the sibling phenotypes.
- Quetiapine, Tacrolimus (representative affected medicines).
- Category:Pharmacogenomic phenotypes
References
- ↑ Wang D, Guo Y, Wrighton SA, Cooke GE, Sadee W. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. The Pharmacogenomics Journal. 2011 Aug;11(4):274-286. PMID: 20386561.
- ↑ Dutch Pharmacogenetics Working Group (DPWG). Gene-drug interaction guideline for CYP3A4 (PharmGKB guideline annotation PA166265421). Royal Dutch Pharmacists Association (KNMP). Available via https://www.pharmgkb.org/.