From the Guidelines
Increased CYP2C19 allele enzyme activity can lead to enhanced metabolism of certain medications, potentially resulting in reduced efficacy or increased risk of adverse effects, and healthcare providers should consider genetic testing to optimize dosing and therapeutic outcomes. The impact of increased CYP2C19 allele enzyme activity on drug metabolism is significant, as it can affect the breakdown of various medications, including clopidogrel, proton pump inhibitors like omeprazole, certain antidepressants, and some antifungals 1. This genetic variant is associated with an ultrarapid metabolizer phenotype, which accelerates the metabolism of drugs processed by the CYP2C19 enzyme. For example, increased CYP2C19 activity may lead to enhanced antiplatelet effects and potentially increased bleeding risk with clopidogrel, while reduced efficacy may occur with proton pump inhibitors due to faster drug clearance 1. Clinically, patients with increased CYP2C19 allele enzyme activity may require higher doses of these medications or alternative medications that are not metabolized by this pathway to achieve therapeutic effects. Key points to consider include:
- Genetic testing for CYP2C19 status can help optimize dosing and therapeutic outcomes
- Increased CYP2C19 activity can affect the metabolism of various medications, including clopidogrel and proton pump inhibitors
- Alternative medications or higher doses may be necessary to achieve therapeutic effects in patients with increased CYP2C19 allele enzyme activity
- Healthcare providers should be aware of the potential impact of CYP2C19 genotype on drug metabolism and adjust treatment strategies accordingly, as supported by recent studies 1.
From the FDA Drug Label
Use of drugs that induce the activity of CYP2C19 would be expected to result in increased drug levels of the active metabolite of clopidogrel and might potentiate the bleeding risk. The impact of increased CYP2C19 allele enzyme activity is an increased risk of bleeding due to higher levels of the active metabolite of clopidogrel 2.
- Key points:
- Increased CYP2C19 activity may potentiate the bleeding risk
- Avoid concomitant use of strong CYP2C19 inducers to minimize this risk 2
From the Research
Impact of Increased CYP2C19 Allele Enzyme Activity
- The CYP2C19*17 allele has been associated with increased transcriptional activity and extensive metabolism of CYP2C19 substrates 3, 4, 5, 6.
- Studies have shown that individuals with the CYP2C19*17 allele have lower platelet aggregation values compared to those with the wild-type allele, indicating increased metabolism of clopidogrel 3.
- The CYP2C19*17 allele has also been linked to increased metabolism of other drugs, including proton pump inhibitors and antidepressants 4, 6.
- Research has found that the CYP2C19*17 allele is associated with decreased metabolic ratios for certain drugs, such as citalopram and amitriptyline, indicating increased enzyme activity 6.
- The increased activity of the CYP2C19*17 allele may lead to therapeutic failures or reduced efficacy of certain drugs, highlighting the importance of considering genetic variations in drug metabolism 4, 6.
- Transcriptional regulation of CYP2C19 plays a crucial role in determining its enzyme activity, and genetic variations in the promoter region may alter the interaction with transcription factors, leading to variable transcription 7.