Phenotype:CYP2C9 normal metabolizer

A CYP2C9 normal metabolizer (NM) is a person whose CYP2C9 alleles together produce the typical, reference level of enzyme activity. It is one of the three metabolizer phenotypes assigned from CYP2C9 genotype, above the poor metabolizer and intermediate metabolizer. CYP2C9 has no rapid or ultrarapid phenotype, so the normal metabolizer is the highest-activity phenotype on the scale. This page describes the normal-metabolizer phenotype; the enzyme itself is covered at Enzyme:CYP2C9.

The normal metabolizer is the reference phenotype. Standard, label-recommended doses of CYP2C9-affected medicines, and the standard starting doses of warfarin and phenytoin, are calibrated to normal-metabolizer populations. For a normal metabolizer, CYP2C9 genotype is not a reason to depart from standard dosing.

Genotype basis

The normal-metabolizer phenotype is produced by the \*1/\*1 diplotype, two normal-function alleles. The full allele catalogue is maintained at PharmVar and described on the Enzyme:CYP2C9 page.

Population frequency

The CYP2C9 normal-metabolizer phenotype is the most common phenotype in most populations, though less overwhelmingly so in European-ancestry populations than elsewhere, because the reduced-function \*2 and \*3 alleles are frequent enough there that the intermediate-metabolizer phenotype claims a substantial share of the population.

Clinical significance

For a CYP2C9 normal metabolizer, standard dosing of CYP2C9-affected medicines applies, and no genotype-based dose adjustment is indicated. Warfarin can be initiated at its standard dose, and phenytoin and the CYP2C9-cleared NSAIDs require no genotype-driven reduction.

Two caveats apply, as for any normal-metabolizer phenotype. First, the normal metabolizer is the phenotype most readily phenocopied: co-prescription of a strong CYP2C9 inhibitor, in particular fluconazole or amiodarone, converts the patient functionally into an intermediate or poor metabolizer for the duration of the inhibition. A normal-metabolizer genotype offers no protection against that interaction; the classic warning is the sharp warfarin INR rise after fluconazole is added. Second, normal-metabolizer status addresses the CYP2C9 variable only, not the many other determinants of a medicine's effect, which for warfarin in particular include VKORC1 genotype, diet, age, and concurrent illness.

See also

• Enzyme:CYP2C9, the enzyme, its history, and its full substrate spectrum.
• Phenotype:CYP2C9 poor metabolizer, Phenotype:CYP2C9 intermediate metabolizer, the sibling phenotypes.
• Enzyme:VKORC1, the warfarin-target gene dosed together with CYP2C9.
• Category:Pharmacogenomic phenotypes