Phenotype:CYP2C9 poor metabolizer
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A CYP2C9 poor metabolizer (PM) is a person who carries two decreased-function or no-function CYP2C9 alleles and therefore has substantially reduced CYP2C9 enzyme activity. It is one of the three metabolizer phenotypes assigned from CYP2C9 genotype, the others being the intermediate metabolizer and the normal metabolizer. CYP2C9 has no ultrarapid phenotype: gain-of-function alleles are not established for this enzyme, so the phenotype scale runs only from poor to normal. This page describes the poor-metabolizer phenotype; the enzyme itself is covered at Enzyme:CYP2C9.
CYP2C9 is, for almost all of its clinically important substrates, a clearance enzyme rather than an activating one, so the poor-metabolizer story is mostly a single story: medicines that depend on CYP2C9 for elimination are cleared slowly, accumulate, and reach concentrations at which their dose-related toxicities appear. Because several of those medicines have narrow therapeutic windows, the poor-metabolizer phenotype is one of the more consequential in clinical pharmacogenomics.
Genotype basis
The poor-metabolizer phenotype is produced by a CYP2C9 diplotype combining two decreased-function or no-function alleles. The clinically important alleles:
- \*2 (rs1799853, Arg144Cys), a decreased-function allele, common in European-ancestry populations.
- \*3 (rs1057910, Ile359Leu), a more severely decreased-function allele retaining only a small fraction of normal activity, also common in European-ancestry populations.
- \*5, \*6, \*8, \*11, decreased- or no-function alleles that are more frequent in African-ancestry populations and are often missed by genotyping panels designed around the European-ancestry alleles.
Diplotypes such as \*3/\*3, \*2/\*3, and \*8/\*8 produce the poor-metabolizer phenotype. The full allele catalogue is maintained at PharmVar and described on the Enzyme:CYP2C9 page.
Population frequency
The CYP2C9 poor-metabolizer phenotype is uncommon in all well-studied populations, because it requires two reduced-function alleles. It is the intermediate-metabolizer phenotype, carrying a single reduced-function allele, that is common, particularly in European-ancestry populations where \*2 and \*3 are frequent.
Clinical consequences
The guidance below follows the Clinical Pharmacogenetics Implementation Consortium (CPIC).
Warfarin. A CYP2C9 poor metabolizer clears the active S-enantiomer of warfarin slowly and requires a substantially lower dose; given a standard dose, the poor metabolizer is at elevated risk of over-anticoagulation and bleeding. CPIC's warfarin guideline combines CYP2C9 genotype with VKORC1 genotype and clinical factors in a dosing algorithm, and the combination of reduced-function CYP2C9 and reduced-function VKORC1 calls for a particularly low starting dose.[1]
Phenytoin. CPIC recommends that a CYP2C9 poor metabolizer receive roughly 50% of the standard maintenance dose of phenytoin, because the medicine's nonlinear pharmacokinetics make reduced clearance translate into large rises in plasma concentration and toxicity.[2]
NSAIDs. For the CYP2C9-cleared NSAIDs, in particular the longer-half-life agents such as piroxicam and meloxicam, a poor metabolizer accumulates the medicine and faces increased gastrointestinal and renal toxicity. CPIC recommends a reduced dose or selection of an NSAID not dependent on CYP2C9.[3]
The activation exception: losartan. The angiotensin-receptor blocker losartan is the one common CYP2C9 substrate for which the enzyme performs an activation rather than a clearance. CYP2C9 converts losartan to its more potent metabolite E-3174, so a poor metabolizer generates less active metabolite and may have a reduced antihypertensive response, the opposite direction of effect from the clearance substrates above.
Phenocopying
A genetically normal metabolizer co-prescribed a strong CYP2C9 inhibitor, in particular fluconazole or amiodarone, behaves functionally as a poor or intermediate metabolizer for the duration of the inhibition. The classic clinical signature is a sharp rise in warfarin INR within days of starting fluconazole in a previously stable patient.
See also
- Enzyme:CYP2C9, the enzyme, its history, and its full substrate spectrum.
- Phenotype:CYP2C9 intermediate 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.