Phenotype:CYP2C19 poor metabolizer
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A CYP2C19 poor metabolizer (PM) is a person who carries two no-function CYP2C19 alleles and therefore produces little or no functional CYP2C19 enzyme. It is one of the five metabolizer phenotypes assigned from CYP2C19 genotype, the others being the intermediate metabolizer, the normal metabolizer, the rapid metabolizer, and the ultrarapid metabolizer. This page describes the poor-metabolizer phenotype; the enzyme itself, its history, and its full substrate range are covered at Enzyme:CYP2C19.
As for any metabolizer phenotype, the clinical effect runs in two opposite directions depending on what CYP2C19 does to the medicine. For a medicine that CYP2C19 activates from a prodrug, the poor metabolizer generates too little of the active form. For a medicine that CYP2C19 clears, the poor metabolizer accumulates it. The single most important instance is the antiplatelet prodrug clopidogrel, and it is an activation case.
Genotype basis
The poor-metabolizer phenotype is produced by a CYP2C19 diplotype in which both alleles are no-function alleles. The two that matter most:
- \*2 (rs4244285), a splice-defect no-function allele and the most common loss-of-function CYP2C19 allele worldwide.
- \*3 (rs4986893), a premature-stop no-function allele, largely confined to East Asian populations.
Diplotypes such as \*2/\*2, \*2/\*3, and \*3/\*3 produce the poor-metabolizer phenotype. The full allele catalogue is maintained at PharmVar and described on the Enzyme:CYP2C19 page.
Population frequency
The CYP2C19 poor-metabolizer phenotype is found in roughly 2 to 5% of European-ancestry populations, 13 to 23% of East Asian populations, and about 4% of African-ancestry populations. The much higher frequency in East Asian populations, driven by the \*2 and \*3 alleles, has direct public-health weight: in an East Asian population, close to one patient in five prescribed clopidogrel is a poor metabolizer.
Clinical consequences
Clopidogrel (activation; reduced effect). Clopidogrel is an antiplatelet prodrug that CYP2C19 converts, in a key step, to its active thiol metabolite. A poor metabolizer generates substantially less active metabolite, obtains less platelet inhibition, and has a higher risk of stent thrombosis and major adverse cardiovascular events after percutaneous coronary intervention. CPIC recommends an alternative antiplatelet agent, prasugrel or ticagrelor, for poor metabolizers in that setting, a recommendation carrying CPIC's strongest classification.[1]
Proton pump inhibitors (clearance; raised exposure). Omeprazole and the other CYP2C19-cleared proton pump inhibitors reach higher plasma concentrations in a poor metabolizer, which tends to mean better acid suppression at a standard dose. CPIC notes this is often clinically favourable for short-term treatment, with the caveat that exposure-related effects can accumulate over long-term therapy.[2]
SSRIs (clearance; raised exposure). For citalopram and escitalopram, a poor metabolizer reaches higher exposures and a meaningfully elevated risk of QT-interval prolongation. CPIC recommends a 50% reduction of the starting dose, or selection of an antidepressant not metabolized by CYP2C19.[3]
Voriconazole (clearance; raised exposure). A poor metabolizer reaches substantially higher voriconazole exposures, with an increased risk of hepatotoxicity; genotype can guide a lower starting dose, and therapeutic drug monitoring is the usual clinical lever.
Phenocopying
A genetically normal metabolizer co-prescribed a strong CYP2C19 inhibitor, in particular fluvoxamine or fluoxetine, or the substrate-and-inhibitor omeprazole, behaves functionally as a poor or intermediate metabolizer for the duration of the inhibition. The clopidogrel interaction deserves specific attention here: a patient stabilised on clopidogrel who is started on omeprazole has, in effect, been pushed toward the poor-metabolizer phenotype for the medicine that depends on CYP2C19 activation.
See also
- Enzyme:CYP2C19, the enzyme, its history, and its full substrate spectrum.
- Phenotype:CYP2C19 intermediate metabolizer, Phenotype:CYP2C19 normal metabolizer, Phenotype:CYP2C19 rapid metabolizer, Phenotype:CYP2C19 ultrarapid metabolizer, the sibling phenotypes.
- Clopidogrel, Omeprazole, Escitalopram (representative affected medicines).
- Category:Pharmacogenomic phenotypes
References
- ↑ Lee CR, Luzum JA, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update. Clinical Pharmacology and Therapeutics. 2022 Nov;112(5):959-967. PMID: 35034351.
- ↑ Lima JJ, Thomas CD, Barbarino J, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C19 and Proton Pump Inhibitor Dosing. Clinical Pharmacology and Therapeutics. 2021 Jun;109(6):1417-1423. PMID: 32770672.
- ↑ Bousman CA, Stevenson JM, Ramsey LB, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants. Clinical Pharmacology and Therapeutics. 2023 Jul;114(1):51-68. PMID: 37032427.