Enzyme:CYP2C19: Difference between revisions

CYP2C19 catalyzes hydroxylation and dealkylation of an unusually focused set of substrates, in marked contrast to the catholic substrate spectrum of [[Enzyme:CYP3A4|CYP3A4]]. The substrates that matter most in current practice:

* '''[[Clopidogrel|Clopidogrel]]''' (Plavix). The antiplatelet effect of clopidogrel depends on a two-step bioactivation, the second of which is performed by CYP2C19, converting the parent compound to the thiol metabolite that covalently inactivates the platelet P2Y12 receptor. Poor metabolizers generate substantially less of the active metabolite and obtain less antiplatelet effect, which translates clinically into higher rates of stent thrombosis and major adverse cardiovascular events after percutaneous coronary intervention. CPIC recommends alternative antiplatelet therapy (prasugrel or ticagrelor) for poor and intermediate metabolizers in the post-PCI setting; the recommendation carries CPIC's strongest classification.<ref name="cpic-clopidogrel-2022">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.</ref> The FDA has carried a boxed warning on clopidogrel's diminished effectiveness in CYP2C19 poor metabolizers since 2010.

* '''Proton pump inhibitors''': [[Omeprazole|omeprazole]], esomeprazole, pantoprazole, lansoprazole, dexlansoprazole are all cleared predominantly by CYP2C19 (rabeprazole less so, since it relies more heavily on a non-enzymatic pathway). Poor metabolizers reach higher plasma concentrations and have better acid suppression at standard doses, while rapid and ultrarapid metabolizers may underrespond. CPIC publishes phenotype-specific dosing guidance, recommending dose increases in rapid and ultrarapid metabolizers and consideration of dose decreases or alternative agents in poor metabolizers, especially during long-term therapy where exposure-related side effects accumulate.<ref name="cpic-ppi-2021">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.</ref>

* '''SSRIs''': [[Citalopram|citalopram]], [[Escitalopram|escitalopram]], and to a smaller degree [[Sertraline|sertraline]] are CYP2C19 substrates. Poor metabolizers have higher exposures and a meaningfully elevated risk of QT-interval prolongation on citalopram and escitalopram; CPIC recommends a 50% starting-dose reduction or selection of an alternative antidepressant for poor metabolizers, and consideration of an alternative for ultrarapid metabolizers (in whom subtherapeutic exposures may compromise efficacy).<ref name="cpic-ssri-2023">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.</ref>

* '''Voriconazole''': poor metabolizers have substantially higher plasma exposures and an increased risk of hepatotoxicity; ultrarapid metabolizers have subtherapeutic exposures and risk treatment failure. Therapeutic drug monitoring is the usual clinical lever, but CYP2C19 genotype can pre-emptively guide the starting dose.

* '''Other substrates of interest''': diazepam (the N-demethylation step), phenytoin (a partial pathway alongside CYP2C9), the tricyclic antidepressants (partial), the antimalarial proguanil (which CYP2C19 activates to cycloguanil).

The harmonized CPIC + DPWG phenotype-translation table for CYP2C19 distinguishes five categories rather than the four used for CYP2D6, reflecting the importance of the gain-of-function ''*17'' allele.<ref name="cpic-clopidogrel-2022" />

* '''Known PM phenotype''': avoid prodrugs that require CYP2C19 activation ([[Clopidogrel|clopidogrel]] should be replaced with prasugrel or ticagrelor in the post-PCI setting). Reduce starting dose by 50% for CYP2C19-cleared agents prone to exposure-related toxicity (citalopram, escitalopram). Consider therapeutic drug monitoring for voriconazole.<ref name="cpic-clopidogrel-2022" /><ref name="cpic-ssri-2023" />

* '''Known UM phenotype''': anticipate undertreatment with prodrugs activated by other CYPs (less of a concern for clopidogrel itself, since UM amplifies activation), and with substrates whose clinical effect depends on exposure (PPIs may underwork; voriconazole levels may be subtherapeutic; some SSRIs may be ineffective). CPIC recommends dose increases for PPIs and alternative-agent consideration for SSRIs in this phenotype.<ref name="cpic-ppi-2021" /><ref name="cpic-ssri-2023" />