Phenotype:CYP3A4 normal metabolizer

A CYP3A4 normal metabolizer (NM) is a person who carries two normal-function CYP3A4 alleles and therefore has the typical, reference level of 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), above the poor metabolizer and intermediate metabolizer. This page describes the normal-metabolizer phenotype; the enzyme itself is covered at Enzyme:CYP3A4.

As noted on the sibling phenotype pages, the CYP3A4 phenotype classification is a DPWG construct and is not endorsed by the Clinical Pharmacogenetics Implementation Consortium, which does not tier CYP3A4.

Genotype basis

The normal-metabolizer phenotype is produced by the \*1/\*1 diplotype, two normal-function alleles, that is, the absence of the decreased-function CYP3A4\*22 allele (rs35599367), the intron-6 variant that reduces CYP3A4 transcription. The full allele catalogue is described on the Enzyme:CYP3A4 page.

Population frequency

Because the \*22 allele is uncommon, with a frequency of only roughly 5 to 8% even in the European-ancestry populations where it is most frequent, the great majority of people are CYP3A4 normal metabolizers. The CYP3A4 normal-metabolizer phenotype is the overwhelmingly dominant phenotype in every population.

Clinical significance

For a CYP3A4 normal metabolizer, the framework of the Dutch Pharmacogenetics Working Group (DPWG) prescribes no genotype-based dose adjustment: standard dosing of CYP3A4-cleared medicines applies.

For CYP3A4 more than for any other enzyme in this set, however, a normal-metabolizer genotype is weak reassurance, and the reason is the one stated throughout the CYP3A4 pages. CYP3A4 activity is dominated by induction and inhibition, not by inherited genetics. A CYP3A4 normal metabolizer taking a strong CYP3A4 inhibitor, such as ketoconazole, clarithromycin, ritonavir, or the furanocoumarins of grapefruit juice, will have CYP3A4 activity far below that of an untreated poor metabolizer. A CYP3A4 normal metabolizer taking a strong inducer such as rifampin will have CYP3A4 activity far above baseline. The genotype describes the resting state of an enzyme whose working activity is set, in practice, mostly by what else the patient is taking. Of the metabolizer phenotypes in this category, the CYP3A4 normal metabolizer is the one for which the phenotype label carries the least predictive weight on its own.

See also

• Enzyme:CYP3A4, the enzyme, its history, and its full substrate spectrum.
• Phenotype:CYP3A4 poor metabolizer, Phenotype:CYP3A4 intermediate metabolizer, the sibling phenotypes.
• Ketoconazole, Rifampin (a strong CYP3A4 inhibitor and a strong inducer, the dominant determinants of CYP3A4 activity).
• Category:Pharmacogenomic phenotypes