Phenotype:CYP2C19 ultrarapid metabolizer
A CYP2C19 ultrarapid metabolizer (UM) is a person whose CYP2C19 alleles together produce the highest level of enzyme activity in the phenotype scale, above the rapid metabolizer, normal metabolizer, intermediate metabolizer, and poor metabolizer. This page describes the ultrarapid-metabolizer phenotype; the enzyme itself is covered at Enzyme:CYP2C19.
Genotype basis
The ultrarapid-metabolizer phenotype is produced by the \*17/\*17 diplotype: two copies of the increased-function \*17 allele, a promoter-region variant that raises CYP2C19 transcription. The full allele catalogue is maintained at PharmVar and described on the Enzyme:CYP2C19 page.
Population frequency
The CYP2C19 ultrarapid-metabolizer phenotype is found in roughly 2 to 5% of European-ancestry populations and is rare in East Asian populations, tracking the distribution of the \*17 allele.
Clinical consequences
Clopidogrel (activation). An ultrarapid metabolizer activates clopidogrel at least as efficiently as a normal metabolizer, so the loss-of-antiplatelet-effect concern that defines the poor- and intermediate-metabolizer phenotypes does not apply. CPIC advises standard, label-recommended clopidogrel use for ultrarapid metabolizers.[1]
Proton pump inhibitors (clearance; reduced exposure). An ultrarapid metabolizer clears the CYP2C19-dependent proton pump inhibitors quickly, reaching low plasma concentrations and risking inadequate acid suppression at a standard dose. CPIC recommends considering an increased proton-pump-inhibitor dose for ultrarapid metabolizers, particularly where reliable acid suppression is clinically important.[2]
SSRIs (clearance; reduced exposure). For citalopram and escitalopram, an ultrarapid metabolizer reaches subtherapeutic exposures at a standard dose, with a real risk that the antidepressant simply does not work. CPIC recommends considering an antidepressant not metabolized by CYP2C19.[3]
Voriconazole (clearance; reduced exposure). An ultrarapid metabolizer reaches subtherapeutic voriconazole concentrations and is at risk of antifungal treatment failure; genotype can prompt a higher starting dose, with therapeutic drug monitoring.
See also
- Enzyme:CYP2C19, the enzyme, its history, and its full substrate spectrum.
- Phenotype:CYP2C19 poor metabolizer, Phenotype:CYP2C19 intermediate metabolizer, Phenotype:CYP2C19 normal metabolizer, Phenotype:CYP2C19 rapid 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.