Enzyme:CYP2C19

CYP2C19 (cytochrome P450 2C19) is a hepatic drug-metabolizing enzyme whose genetic polymorphism is the most clinically actionable in routine prescribing after CYP2D6. It is encoded by the CYP2C19 gene on chromosome 10q23.33 and accounts for roughly 5 to 10% of total hepatic CYP protein. Three areas of medicine sit squarely on its activity: the antiplatelet clopidogrel (a prodrug that requires CYP2C19 to be activated to its working form), the proton pump inhibitors used to suppress gastric acid, and several of the SSRI antidepressants and the antifungal voriconazole. Population frequency of the poor-metabolizer phenotype varies markedly by ancestry, which has clinical and ethical implications the wiki returns to below.

Function and substrate spectrum

CYP2C19 catalyzes hydroxylation and dealkylation of an unusually focused set of substrates, in marked contrast to the catholic substrate spectrum of CYP3A4. The substrate list is short but contains medicines whose narrow therapeutic indices, complex prodrug-activation pharmacology, and large population-frequency variation in CYP2C19 metabolizer phenotype have made the enzyme one of the most clinically actionable pharmacogenomic loci in routine prescribing.

The table below collects the clinically important CYP2C19 substrates with each entry tagged by the contribution CYP2C19 makes to overall clearance (or to bioactivation, where the relevant medicine is a CYP2C19-activated prodrug): major (CYP2C19 is the predominant route), moderate (CYP2C19 contributes meaningfully but other routes carry comparable load), minor (CYP2C19 contributes but other pathways dominate), and partial (one of several substantial routes). The list is curated for clinical relevance and is not exhaustive; see Comprehensive substrate and interaction tables below for the authoritative maintained resources.

near-complete CYP2C19 substrate table (click to expand)

Substrate	Therapeutic class	CYP2C19 contribution	Clinical notes
Amitriptyline	Tricyclic antidepressant	partial	N-demethylation to nortriptyline is partly CYP2C19; CYP2D6 dominates the hydroxylation step.
Carisoprodol	Muscle relaxant	major	PMs have substantially higher exposures and prolonged sedation.
Citalopram	SSRI antidepressant	major	CPIC SSRI guideline: CYP2C19 PMs at elevated QT-prolongation risk; 50% starting-dose reduction or alternative agent recommended.
Clobazam	Benzodiazepine (antiepileptic)	major	N-demethylation to the active norclobazam metabolite; PMs accumulate norclobazam to higher levels.
Clopidogrel	Antiplatelet (P2Y12 inhibitor prodrug)	major	Activation reaction; FDA boxed warning. CYP2C19 performs the second activation step. PMs generate substantially less active metabolite, with higher rates of stent thrombosis post-PCI. CPIC strongly recommends prasugrel or ticagrelor instead in PM/IM.
Clomipramine	Tricyclic antidepressant	partial	N-demethylation to desmethylclomipramine; mixed CYP2C19 + CYP2D6.
Cyclophosphamide	Antineoplastic (alkylating)	partial	Bioactivation route is multi-CYP (CYP2B6 dominant, CYP2C19 and CYP3A4 contributing).
Dexlansoprazole	Proton pump inhibitor	major	Same CYP2C19-dependence as lansoprazole.
Diazepam	Benzodiazepine	major	N-demethylation to nordiazepam (the long-half-life active metabolite). PMs accumulate diazepam and nordiazepam to higher exposures.
Escitalopram	SSRI antidepressant	major	CPIC SSRI guideline: same QT and dose-adjustment caution pattern as citalopram.
Esomeprazole	Proton pump inhibitor	major	Same CYP2C19-dependence as omeprazole (esomeprazole is the S-enantiomer of omeprazole).
Imipramine	Tricyclic antidepressant	partial	N-demethylation to desipramine.
Indomethacin	NSAID	partial	Mixed CYP2C19 + glucuronidation; CYP2C19 minor relative to CYP2C9 in NSAID metabolism generally.
Lansoprazole	Proton pump inhibitor	major	CPIC PPI guideline: dose increase in RM/UM; consider dose reduction in PM.
Mephenytoin	Antiepileptic (historical)	major	The original probe substrate for the CYP2C19 polymorphism (the "mephenytoin hydroxylase deficiency" phenotype, by which the enzyme was originally characterised in the 1980s).
Moclobemide	Reversible MAO-A inhibitor (antidepressant)	major	PMs have higher exposures.
Nelfinavir	HIV protease inhibitor	major	PMs have higher exposures.
Omeprazole	Proton pump inhibitor	major	Canonical CYP2C19 substrate. PMs have higher acid-suppression at standard doses; UMs may underrespond. Also a moderate CYP2C19 self-inhibitor, with the clinical-relevance kink that this attenuates clopidogrel activation.
Pantoprazole	Proton pump inhibitor	major	Weaker CYP2C19 inhibitor than omeprazole, so generally preferred when a PPI is co-prescribed with clopidogrel.
Phenobarbital	Barbiturate (antiepileptic, sedative)	partial	Mixed CYP2C19 + CYP2C9 + non-CYP routes.
Phenytoin	Antiepileptic	partial	Minor CYP2C19 route alongside the dominant CYP2C9 pathway; relevant in CYP2C9 PMs in whom the CYP2C19 contribution becomes proportionally larger.
Proguanil	Antimalarial (prodrug)	major	Activation reaction. CYP2C19 converts proguanil to cycloguanil, the active dihydrofolate-reductase inhibitor. PMs have reduced antimalarial efficacy.
Propranolol	Beta blocker	partial	Mixed CYP2C19 + CYP1A2 + CYP2D6 routes.
Rabeprazole	Proton pump inhibitor	partial	Less CYP2C19-dependent than other PPIs because it relies more heavily on non-enzymatic reduction; CYP2C19 contribution still real but smaller.
Sertraline	SSRI antidepressant	partial	Mixed CYP2C19 + CYP2B6 + CYP2D6 + CYP3A4; less CYP2C19-dependent than citalopram or escitalopram.
Thalidomide	Immunomodulator (myeloma, leprosy)	moderate	Mixed CYP2C19 + non-enzymatic hydrolysis.
Voriconazole	Triazole antifungal	major	PMs have substantially higher exposures and hepatotoxicity risk; UMs have subtherapeutic exposures and treatment-failure risk. Therapeutic drug monitoring is standard, but CYP2C19 genotype can guide the starting dose.
Warfarin	Anticoagulant	minor	R-warfarin is a minor CYP2C19 substrate; the clinically dominant CYP2C9-mediated metabolism of S-warfarin overshadows it.

Phenotype categories

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.

Phenotype	Abbreviation	Diplotype (typical)	Approximate frequency
Poor metabolizer	PM	two no-function alleles	2–5% European, 13–23% East Asian, 4% African
Intermediate metabolizer	IM	one no-function + one normal-function (or *2/*17, *3/*17, etc.)	24–36% (varies by ancestry)
Normal metabolizer	NM	two normal-function alleles (*1/*1)	35–45%
Rapid metabolizer	RM	one normal-function + one increased-function (*1/*17)	18–26% European, lower elsewhere
Ultrarapid metabolizer	UM	two increased-function alleles (*17/*17)	2–5% European, very rare in East Asian populations

The PM frequency variation by ancestry has practical consequences. In East Asian populations roughly one in five patients prescribed clopidogrel will be a CYP2C19 PM with diminished antiplatelet response, a public-health-scale signal that has driven routine pre-PCI genotyping in some health systems. In European-ancestry populations PMs are uncommon but RMs and UMs (driven by the *17 allele) are common enough that the gain-of-function tail of the distribution matters for the PPI and SSRI guidelines.

Major star alleles

The full allele catalog is maintained at PharmVar. The clinically dominant ones:

• *1, reference, fully functional (activity 1.0)
• *2 (rs4244285, c.681G>A, splice-defect), no function (activity 0). The most common loss-of-function allele worldwide. Frequency roughly 15% in European-ancestry, 25 to 30% in East Asian, 17% in African-ancestry populations.
• *3 (rs4986893, c.636G>A, premature stop), no function (activity 0). Largely an East Asian allele, frequency around 5%, rare elsewhere.
• *4, *5, *6, *7, *8, other rare no-function variants catalogued at PharmVar.
• *17 (rs12248560, c.-806C>T, promoter TATA-box variant), increased function. Increases transcription and produces a roughly 1.5-fold rise in enzyme activity. Frequency roughly 21% in European-ancestry, 18% in African-ancestry, 4% in East Asian populations. The driver of the Rapid and Ultrarapid metabolizer phenotypes.

A diplotype like *1/*2 produces an intermediate metabolizer; *2/*2 produces a poor metabolizer; *1/*17 a rapid metabolizer; *17/*17 an ultrarapid metabolizer. The *2/*17 combination is treated as intermediate per the current consensus, because the loss-of-function effect of *2 outweighs the gain-of-function effect of *17 at the diplotype level.

Inhibitors

CYP2C19 inhibition produces phenocopy poor or intermediate metabolism for the duration of the inhibitor's effect. Strong inhibitors of clinical relevance:

• Omeprazole and esomeprazole, moderate to strong inhibitors (which also happen to be CYP2C19 substrates themselves, since they self-inhibit at therapeutic exposures). This produces the awkward situation of a patient on a PPI plus clopidogrel: PPIs raise omeprazole exposure (good for acid suppression) but reduce clopidogrel activation (bad for antiplatelet effect). Pantoprazole is a weaker inhibitor and is generally preferred as the PPI co-prescribed with clopidogrel when one is needed.
• Fluvoxamine, a strong CYP2C19 inhibitor (and a strong CYP1A2 inhibitor as well). Substantial clopidogrel-effect attenuation in healthy-volunteer studies.
• Fluoxetine, moderate to strong inhibitor, with the same long inhibition tail (4 to 6 weeks after discontinuation) as it has at CYP2D6 because of norfluoxetine.
• Modafinil, moderate inhibitor.
• Ticlopidine, strong inhibitor (historically used as an antiplatelet itself; the irony of an antiplatelet that inhibits the activation of a different antiplatelet is part of why ticlopidine has fallen out of use).

Inducers

CYP2C19 is inducible by the same PXR/CAR-mediated pathway that induces CYP3A4, though the magnitude of induction is generally smaller. Rifampin is the canonical strong inducer, reducing exposures of CYP2C19 substrates by roughly 50 to 80%. Other inducers include carbamazepine, phenytoin (which is also a substrate, producing autoinduction), ritonavir at chronic dosing, and St John's Wort. The slow-on / slow-off kinetic profile that characterizes CYP3A4 induction applies here too, and the window after discontinuing an inducer can produce rising substrate exposures over 1 to 3 weeks.

Clinical implications, summary

For any medicine that depends materially on CYP2C19 for activation or clearance:

• Known PM phenotype: avoid prodrugs that require CYP2C19 activation (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.
• 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.
• Standard genotype + strong CYP2C19 inhibitor co-prescribed (especially fluvoxamine, fluoxetine, or omeprazole): treat as phenocopy intermediate or poor metabolizer for the duration of the inhibitor's effect. Watch the clopidogrel co-prescription specifically; switch to pantoprazole or H2-blocker if a PPI is needed.
• Pre-prescription genotyping: increasingly routine before clopidogrel initiation in cardiology, especially in health systems serving populations with high PM frequency. Less routine for the PPI and SSRI indications, where alternatives are inexpensive and therapeutic-drug-monitoring substitutes are available.

Comprehensive substrate and interaction tables

The substrate and interaction tables on this page are curated for clinical relevance, not for completeness. Three authoritative external resources maintain comprehensive lists of CYP2C19 substrates, inhibitors, and inducers, and the wiki recommends them to any reader who needs an exhaustive look-up:

• Flockhart Cytochrome P450 Drug Interaction Table, maintained by the Department of Medicine at Indiana University School of Medicine. The most widely cited clinical-reference cytochrome P450 table; substrate-, inhibitor-, and inducer-tiered, updated regularly. Available at https://drug-interactions.medicine.iu.edu/.
• U.S. Food and Drug Administration Drug Development and Drug Interactions Table, the regulatory-grade list FDA uses for labeling and clinical-trial design decisions. Smaller than Flockhart but every entry is FDA-vetted. Available via the FDA Center for Drug Evaluation and Research clinical drug interaction page.
• PharmGKB, the pharmacogenomics knowledge base hosted at Stanford University; the CYP2C19 gene page indexes substrate-, inhibitor-, and inducer-relationships with their underlying primary literature, and links each gene-drug pair to the CPIC dosing guideline where one exists. Available at https://www.pharmgkb.org/.

For a comprehensive review of CYP2C19 (and the rest of the human cytochrome P450 family) covering regulation, polymorphism, and substrate spectrum in detail, the Zanger and Schwab 2013 review in Pharmacology and Therapeutics remains the standard reference.

See also

• Phenotype:CYP2C19 poor metabolizer
• Phenotype:CYP2C19 intermediate metabolizer
• Phenotype:CYP2C19 normal metabolizer
• Phenotype:CYP2C19 rapid metabolizer
• Phenotype:CYP2C19 ultrarapid metabolizer
• Enzyme:CYP2D6, Enzyme:CYP3A4, Enzyme:CYP2C9, Enzyme:CYP1A2, Enzyme:CYP2B6
• Clopidogrel, Omeprazole, Escitalopram, voriconazole (canonical clinical examples)
• Fluvoxamine, Fluoxetine (canonical inhibitor examples)
• Rifampin (canonical inducer example)
• Category:Drug-metabolizing enzymes