Phenotype:CYP2C19 rapid metabolizer
A CYP2C19 rapid metabolizer (RM) is a person whose CYP2C19 alleles together produce greater-than-normal enzyme activity, though not as great as the ultrarapid metabolizer. It is one of the five metabolizer phenotypes assigned from CYP2C19 genotype. The existence of a distinct rapid-metabolizer category, between normal and ultrarapid, is a feature CYP2C19 phenotyping has and CYP2D6 phenotyping does not; it exists because of the common gain-of-function \*17 allele. This page describes the rapid-metabolizer phenotype; the enzyme itself is covered at Enzyme:CYP2C19.
Genotype basis
The rapid-metabolizer phenotype is produced by the \*1/\*17 diplotype: one normal-function allele paired with one copy of the increased-function allele.
- \*17 (rs12248560) is a variant in the CYP2C19 promoter region that increases transcription of the gene and raises enzyme activity by roughly 1.5-fold. One copy, alongside a normal-function allele, produces the rapid-metabolizer phenotype; two copies produce the ultrarapid metabolizer.
The full allele catalogue is maintained at PharmVar and described on the Enzyme:CYP2C19 page.
Population frequency
The CYP2C19 rapid-metabolizer phenotype is found in roughly 18 to 26% of European-ancestry populations, where the \*17 allele is common, and at lower frequencies elsewhere. It is uncommon in East Asian populations, where \*17 is rare.
Clinical consequences
Clopidogrel (activation). For clopidogrel, a rapid metabolizer activates the prodrug at least as efficiently as a normal metabolizer, so the antiplatelet concern that dominates the poor- and intermediate-metabolizer pages does not apply: CPIC advises standard, label-recommended clopidogrel use for rapid metabolizers.[1]
Proton pump inhibitors (clearance; reduced exposure). Here the gain of function works against the patient. A rapid metabolizer clears the CYP2C19-dependent proton pump inhibitors faster than a normal metabolizer, reaching lower plasma concentrations and, potentially, weaker acid suppression. CPIC notes that rapid metabolizers may need a higher proton-pump-inhibitor dose to achieve the intended effect, particularly where reliable acid suppression matters, such as in Helicobacter pylori eradication or erosive esophagitis.[2]
SSRIs (clearance; reduced exposure). For citalopram and escitalopram, a rapid metabolizer reaches lower exposures and may, in some patients, underrespond at a standard dose.[3]
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 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.