Phenotype:CYP2C19 intermediate metabolizer
More actions
A CYP2C19 intermediate metabolizer (IM) is a person whose CYP2C19 alleles together produce reduced, but not absent, enzyme activity. It is one of the five metabolizer phenotypes assigned from CYP2C19 genotype, sitting between the poor metabolizer and the normal metabolizer, with the rapid metabolizer and ultrarapid metabolizer above. This page describes the intermediate-metabolizer phenotype; the enzyme itself is covered at Enzyme:CYP2C19.
The intermediate metabolizer is a milder version of the poor metabolizer: a medicine that CYP2C19 activates is activated incompletely, and a medicine that CYP2C19 clears is cleared slowly, but in each case to a lesser degree than in the poor metabolizer.
Genotype basis
The intermediate-metabolizer phenotype is produced by a CYP2C19 diplotype that pairs one normal-function allele with one no-function allele (typically \*1/\*2 or \*1/\*3). The combination of a no-function allele with the increased-function \*17 allele (\*2/\*17 or \*3/\*17) is also classified as intermediate under current consensus, because the loss-of-function effect of the \*2 or \*3 allele outweighs the gain-of-function effect of \*17 at the diplotype level. The full allele catalogue is maintained at PharmVar and described on the Enzyme:CYP2C19 page.
Population frequency
The CYP2C19 intermediate-metabolizer phenotype is found in roughly 24 to 36% of most populations, with the exact figure varying by ancestry with the frequency of the underlying \*2 and \*3 alleles. It is one of the more common metabolizer phenotypes for this gene.
Clinical consequences
Clopidogrel (activation; reduced effect). For clopidogrel, an antiplatelet prodrug activated by CYP2C19, an intermediate metabolizer generates a reduced quantity of the active metabolite and obtains less platelet inhibition than a normal metabolizer. CPIC recommends an alternative antiplatelet agent, prasugrel or ticagrelor, for intermediate metabolizers in the post-percutaneous-coronary-intervention setting, alongside the same recommendation for poor metabolizers.[1]
Proton pump inhibitors and SSRIs (clearance; modestly raised exposure). For the CYP2C19-cleared proton pump inhibitors and for citalopram and escitalopram, an intermediate metabolizer reaches modestly higher exposures than a normal metabolizer. The CPIC guidance for intermediate metabolizers is generally less aggressive than for poor metabolizers: for the SSRIs, intermediate metabolizers are usually managed at standard or near-standard dosing with monitoring rather than the 50% reduction advised for poor metabolizers.[2][3]
Phenocopying
An intermediate metabolizer co-prescribed a strong CYP2C19 inhibitor (fluvoxamine, fluoxetine, omeprazole) can be pushed functionally into the poor-metabolizer range. Because the intermediate metabolizer begins with reduced activity, the margin before clinically significant loss of function is smaller than for a normal metabolizer.
See also
- Enzyme:CYP2C19, the enzyme, its history, and its full substrate spectrum.
- Phenotype:CYP2C19 poor metabolizer, Phenotype:CYP2C19 normal metabolizer, Phenotype:CYP2C19 rapid metabolizer, Phenotype:CYP2C19 ultrarapid metabolizer, the sibling phenotypes.
- Clopidogrel, 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.