Phenotype:CYP2C9 intermediate metabolizer
A CYP2C9 intermediate metabolizer (IM) is a person whose CYP2C9 alleles together produce reduced, but not substantially absent, enzyme activity. It is one of the three metabolizer phenotypes assigned from CYP2C9 genotype, sitting between the poor metabolizer and the normal metabolizer. CYP2C9 has no rapid or ultrarapid phenotype. This page describes the intermediate-metabolizer phenotype; the enzyme itself is covered at Enzyme:CYP2C9.
The intermediate metabolizer is a milder version of the poor metabolizer, and for CYP2C9 it is also the more common of the two reduced phenotypes, because it requires only a single reduced-function allele. In European-ancestry populations, where the \*2 and \*3 alleles are frequent, a substantial fraction of the population is an intermediate metabolizer.
Genotype basis
The intermediate-metabolizer phenotype is produced by a CYP2C9 diplotype that pairs one normal-function allele with one decreased-function or no-function allele, for example \*1/\*2, \*1/\*3, or \*1/\*8. Some diplotypes carrying two mildly decreased-function alleles also fall in the intermediate range. The clinically important reduced-function alleles, \*2 and \*3 (common in European-ancestry populations) and \*5, \*6, \*8, \*11 (more frequent in African-ancestry populations), are described on the Enzyme:CYP2C9 page.
Population frequency
The CYP2C9 intermediate-metabolizer phenotype is common in European-ancestry populations, reflecting the high combined frequency of the \*2 and \*3 alleles. Frequencies differ in other populations with the local prevalence of the reduced-function alleles, which is why an ancestry-aware genotyping panel matters: a panel covering only \*2 and \*3 will under-detect intermediate metabolizers in African-ancestry patients, who more often carry \*5, \*6, \*8, or \*11.
Clinical consequences
The guidance below follows the Clinical Pharmacogenetics Implementation Consortium (CPIC). In each case the intermediate metabolizer shows a milder version of the poor-metabolizer effect.
Warfarin. A CYP2C9 intermediate metabolizer requires a somewhat lower warfarin dose than a normal metabolizer. CPIC's warfarin guideline incorporates CYP2C9 genotype, together with VKORC1 genotype and clinical factors, into a dosing algorithm.[1]
Phenytoin. CPIC recommends that a CYP2C9 intermediate metabolizer receive roughly 75% of the standard maintenance dose of phenytoin, between the standard dose for a normal metabolizer and the roughly 50% dose for a poor metabolizer.[2]
NSAIDs. For the CYP2C9-cleared NSAIDs, CPIC recommends dose reduction or alternative-agent selection for intermediate metabolizers, particularly for the longer-half-life agents prone to accumulation.[3]
Phenocopying
An intermediate metabolizer co-prescribed a strong CYP2C9 inhibitor (fluconazole, amiodarone) can be pushed functionally into the poor-metabolizer range. Because the intermediate metabolizer already starts with reduced activity, the margin before clinically significant loss of function is smaller than for a normal metabolizer, and the warfarin INR rise from an added fluconazole is correspondingly larger.
See also
- Enzyme:CYP2C9, the enzyme, its history, and its full substrate spectrum.
- Phenotype:CYP2C9 poor metabolizer, Phenotype:CYP2C9 normal metabolizer, the sibling phenotypes.
- Enzyme:VKORC1, the warfarin-target gene dosed together with CYP2C9.
- Warfarin, Phenytoin, Celecoxib (representative affected medicines).
- Category:Pharmacogenomic phenotypes
References
- ↑ Johnson JA, Caudle KE, Gong L, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update. Clinical Pharmacology and Therapeutics. 2017 Sep;102(3):397-404. PMID: 28198005.
- ↑ Karnes JH, Rettie AE, Somogyi AA, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing: 2020 Update. Clinical Pharmacology and Therapeutics. 2021 Feb;109(2):302-309. PMID: 32779747.
- ↑ Theken KN, Lee CR, Gong L, et al. Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2C9 and Nonsteroidal Anti-Inflammatory Drugs. Clinical Pharmacology and Therapeutics. 2020 Aug;108(2):191-200. PMID: 32189324.