Phenotype:CYP3A4 poor metabolizer

A CYP3A4 poor metabolizer (PM) is a person who carries two decreased-function CYP3A4 alleles and therefore has 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), the others being the intermediate metabolizer and the normal metabolizer. This page describes the poor-metabolizer phenotype; the enzyme itself is covered at Enzyme:CYP3A4.

A point of context belongs at the top of this page, because it is unusual. CYP3A4 is the only enzyme in the wiki's phenotype set whose metabolizer-phenotype classification is not endorsed by the Clinical Pharmacogenetics Implementation Consortium (CPIC). CPIC does not assign CYP3A4 a poor/intermediate/normal classification, on the view that CYP3A4 activity is governed far more by environmental induction and inhibition than by inherited genetics. The DPWG takes a different position and does define a CYP3A4 phenotype, built on the decreased-function CYP3A4\*22 allele. This page describes that DPWG framework, and the reader should hold in mind throughout that the CYP3A4 poor-metabolizer phenotype is a less settled construct than the long-validated phenotypes of CYP2D6 or CYP2C19.

Genotype basis

The poor-metabolizer phenotype is produced by the \*22/\*22 diplotype: two copies of the decreased-function allele.

• \*22 (rs35599367) is an intron-6 variant of CYP3A4 that reduces transcription of the gene, so that carriers express less CYP3A4 protein and have lower CYP3A4 activity. Its functional effect on enzyme expression and on the response to statin medicines was characterized by Wang and colleagues in 2011.

The full allele catalogue is described on the Enzyme:CYP3A4 page.

Population frequency

The \*22 allele has a frequency of roughly 5 to 8% in European-ancestry populations and is less frequent in other populations. The poor-metabolizer phenotype, which requires two copies, is therefore uncommon; the intermediate-metabolizer phenotype, carrying a single \*22 allele, is the more frequently encountered reduced phenotype.

Clinical consequences

CYP3A4 is, for almost all of its substrates, a clearance enzyme, so the poor-metabolizer story is a clearance story: medicines that depend on CYP3A4 for elimination are cleared slowly and accumulate. The DPWG framework attaches its dosing guidance to that effect. For quetiapine, for example, the DPWG guideline advises that a CYP3A4 poor metabolizer be considered for an alternative medicine, because the reduced clearance raises quetiapine exposure and the risk of its dose-related effects. The \*22 allele has also been associated with a need for lower doses of other CYP3A4 substrates, including tacrolimus and several statins.

A caveat must be stated plainly, and it is larger for CYP3A4 than for any other enzyme in this set. The genetic effect of the \*22 allele is modest next to the effect of CYP3A4 induction and inhibition by co-prescribed medicines, by grapefruit, and by other factors. A CYP3A4 normal metabolizer taking a strong CYP3A4 inhibitor will have far lower CYP3A4 activity than an untreated poor metabolizer. For CYP3A4, the drug-interaction picture is usually the dominant one, and a \*22 genotype is best read as one contributing factor rather than the controlling one.

See also

• Enzyme:CYP3A4, the enzyme, its history, and its full substrate spectrum.
• Phenotype:CYP3A4 intermediate metabolizer, Phenotype:CYP3A4 normal metabolizer, the sibling phenotypes.
• Quetiapine, Tacrolimus, Simvastatin (representative affected medicines).
• Category:Pharmacogenomic phenotypes